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    Clinical Trial Results:
    RCT comparing the analgesic efficacy of 4 therapeutic strategies based on 4 different major opioids (fentanyl, oxycodone, buprenorphine vs morphine) in cancer patients with moderate/severe pain, at the moment of starting 3rd step of WHO analgesic ladder.

    Summary
    EudraCT number
    		 2010-021017-23
    Trial protocol
    		 IT  
    Global end of trial date
    31 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2019
    First version publication date
    28 Mar 2019
    Other versions
    Summary report(s)
    		 Study results

    Trial information

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    Trial identification
    Sponsor protocol code
    STUDIO CERP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01809106
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mario Negri Institute for Pharmacological Research
    Sponsor organisation address
    Via G. La Masa 19, Milan, Italy, 20156
    Public contact
    Oscar Corli, Mario Negri Institute for Pharmacological Research, oscar.corli@marionegri.it
    Scientific contact
    Oscar Corli, Mario Negri Institute for Pharmacological Research, oscar.corli@marionegri.it
    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 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • The comparison of the analgesic efficacy of 4 treatment strategies based on 4 different strong opioids (oral morphine and oxycodone, transdermal fentanyl and buprenorphine) administered by randomization during a 4 weeks follow-up period, in patients with moderate to severe pain due to the cancer, measured at each visit by means of a NRS 0 to 10, and related to the average pain of the previous 24 hours.
    Protection of trial subjects
    It was run according to the Declaration of Helsinki of Good Clinical Practice. Regulatory agencies and local ethics committees approved the study protocol. All patients gave written informed consent.
    Background therapy
    		 --
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 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
    Italy: 518
    Worldwide total number of subjects
    518
    EEA total number of subjects
    518
    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)
    350
    From 65 to 84 years
    168
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 44 sites in Italy from May 2011 to July 2014.

    Pre-assignment
    Screening details
    		 520 patients were randomized and 498 were included in ITT analysis

    Period 1
    Period 1 title
    Study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active comparator
    Arm description
    		 Morphine
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg/day

    Arm title
    		 Experimental
    Arm description
    		 Oxycodone
    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
    40 mg/day

    Arm title
    		 Experimental
    Arm description
    		 Buprenorphine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Buprenorphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    35 µg/h

    Arm title
    		 Experimental
    Arm description
    		 Fentanyl
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fentanyl
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    25 µg/h

    Number of subjects in period 1
    		Active comparator Experimental Experimental Experimental
    Started
    130
    130
    130
    128
    Completed
    122
    125
    127
    124
    Not completed
    8
    5
    3
    4
         Never received treatment
    1
    1
    -
    4
         Lack of efficacy
    7
    4
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active comparator
    Reporting group description
    		 Morphine

    Reporting group title
    Experimental
    Reporting group description
    		 Oxycodone

    Reporting group title
    Experimental
    Reporting group description
    		 Buprenorphine

    Reporting group title
    Experimental
    Reporting group description
    		 Fentanyl

    Reporting group values
    		 Active comparator Experimental Experimental Experimental Total
    Number of subjects
    		 130 130 130 128 518
    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
        arithmetic mean (standard deviation)
    		 67.5 ± 11.7 66.9 ± 11.1 65.2 ± 13.5 68 ± 10.6 -
    Gender categorical
    Units: Subjects
        Female
    		 59 56 60 56 231
        Male
    		 71 74 70 72 287
    Subject analysis sets

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    the intention-to-treat (ITT) population, which included all randomized patients without major violations of the eligibility criteria and with at least one pain evaluation after baseline.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Only patients who started on opioid were included in the safety analysis, which considered patients in the arm of the treatment they actually received. Each patient was considered until the end of the 28-day follow-up, or until a switch or premature discontinuation of the study for any reason.

    Subject analysis sets values
    		 ITT analysis set Safety
    Number of subjects
    498
    515
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.9 ± 11.8
    ±
    Gender categorical
    Units: Subjects
        Female
    221
    229
        Male
    277
    286

    End points

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    End points reporting groups
    Reporting group title
    Active comparator
    Reporting group description
    		 Morphine

    Reporting group title
    Experimental
    Reporting group description
    		 Oxycodone

    Reporting group title
    Experimental
    Reporting group description
    		 Buprenorphine

    Reporting group title
    Experimental
    Reporting group description
    		 Fentanyl

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    the intention-to-treat (ITT) population, which included all randomized patients without major violations of the eligibility criteria and with at least one pain evaluation after baseline.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Only patients who started on opioid were included in the safety analysis, which considered patients in the arm of the treatment they actually received. Each patient was considered until the end of the 28-day follow-up, or until a switch or premature discontinuation of the study for any reason.

    Primary: Proportion of Non-Responder (NR) Participants

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    End point title
    		 Proportion of Non-Responder (NR) Participants
    End point description
    Evaluation of the proportion of Non-Responder (NR) participants. NR correspond to the subjects who do not report any analgesic effects, with a P.I.D. (pain intensity difference) from visit 6 and visit 1 =/< 0%, (using a 0-10 NRS ). It includes the situations of average pain intensity "stable" or "worsened" at day 28 compared with baseline values.
    End point type
    Primary
    End point timeframe
    28 days
    End point values
    		 Active comparator Experimental Experimental Experimental ITT analysis set
    Number of subjects analysed
    122
    125
    127
    124
    498
    Units: Number of patients
    14
    18
    14
    11
    57
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The χ2 test (or Fisher’s exact test, where appropriate) was used to assess differences between oral oxycodone, TD buprenorphine or TD fentanyl, compared with oral morphine.
    Comparison groups
    Experimental v Experimental v Experimental v Active comparator
    Number of subjects included in analysis
    498
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Proportion
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: Proportion of Full-responder

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    End point title
    		 Proportion of Full-responder
    End point description
    Evaluation of the proportion of subjects who report full analgesia (full responders: FR). FR is operationally defined as a patient with a P.I.D. =/> 30% from visit 6 and visit 1 (NRS 0 to 10).
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Active comparator Experimental Experimental Experimental ITT analysis set
    Number of subjects analysed
    122
    125
    127
    124
    498
    Units: Number of patients
    89
    90
    95
    88
    362
    No statistical analyses for this end point

    Other pre-specified: The Opioid Escalation Index

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    End point title
    		 The Opioid Escalation Index
    End point description
    The proportion of subjects with an increase of opioid daily dose > 5% compared with the basal dosage (OEI%).
    End point type
    Other pre-specified
    End point timeframe
    28 days
    End point values
    		 Active comparator Experimental Experimental Experimental
    Number of subjects analysed
    122
    125
    127
    124
    Units: Number of participants
    13
    24
    18
    45
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NA
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Adverse events
    Reporting group description
    		 -

    Serious adverse events
    		 Adverse events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 515 (2.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Hyperalgesia
         subjects affected / exposed
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Exitus
         subjects affected / exposed
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Decline general condition
         subjects affected / exposed
    2 / 515 (0.39%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperpirexia
         subjects affected / exposed
    2 / 515 (0.39%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Bowel occlusion
         subjects affected / exposed
    2 / 515 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Oral cavity bleeding
         subjects affected / exposed
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic disorder
         subjects affected / exposed
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    2 / 515 (0.39%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 515 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Adverse events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    404 / 515 (78.45%)
    General disorders and administration site conditions
    Drowsiness
         subjects affected / exposed
    304 / 515 (59.03%)
         occurrences all number
    1
    Confusional state
         subjects affected / exposed
    221 / 515 (42.91%)
         occurrences all number
    1

    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? Yes
    Date
    Interruption
    Restart date
    31 Jul 2014
    In September 2014, in view of the disappointing recruitment, the Steering Committee decided to early stop enrollment, fully aware that the study could lose the power to test the planned differences between treatments.
    -

    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/26940689
    http://www.ncbi.nlm.nih.gov/pubmed/29220110
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