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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel, 3-Arm Study of the Safety and Anti-Pruritic Efficacy of Nalbuphine HCL ER Tablets in Prurigo Nodularis Patients

    Summary
    EudraCT number
    		 2013-005627-17
    Trial protocol
    		 DE   PL   AT  
    Global end of trial date
    11 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2017
    First version publication date
    29 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TR03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02174419
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Trevi Therapeutics, Inc.
    Sponsor organisation address
    195 Church Street, 14th Floor, New Haven, United States, Connecticut 06510
    Public contact
    Clinical Trial Information, Trevi Therapeutics, Inc., +1 203304-2499, roberta.duncan@trevitherapeutics.com
    Scientific contact
    Clinical Trial Information, Trevi Therapeutics, Inc., +1 203304-2499, roberta.duncan@trevitherapeutics.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
    11 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are: • To evaluate the effects of two doses of nalbuphine HCl ER tablets on the 7-day average daily worst itch (i.e., most severe) intensity during the last 7 days of the Fixed Dose Period (“Evaluation visit”; Visit 5) compared to baseline, as measured by daily electronic patient diary records for the Numerical Rating Scale (NRS) and reported as the proportion of patients with at least a 30% reduction in the baseline 7-day average daily worst itch NRS score • To evaluate the safety and tolerability of nalbuphine HCl ER in the study population
    Protection of trial subjects
    Before the initiation of study-specific procedures, the patients were given a complete explanation of the purpose of the study, evaluations to be conducted, and risks/benefits for study participation. Patients were closely monitored for safety. Adverse events (AEs) were continuously evaluated throughout the study (in particular AEs of special interest: nausea, vomiting, constipation, somnolence, sedation, dizziness, and vertigo and AEs associated with abuse-potential) and vital sign measurements, locally and central cardiac core laboratory 12-lead electrocardiograms (ECGs) readings, physical examination, clinical laboratory testing, and neurological examination were conducted to monitor patient safety. An unblinded, independent Data Safety Monitoring Board (DSMB) periodically reviewed safety data.
    Background therapy
    		 Patients were allowed to receive all clinically indicated medications during the study with the exceptions noted in the study protocol. Rescue Anti-Pruritic Medications: Concomitant use of medications for pruritus (including prior medications that are ongoing and remain at the same dose and dosing frequency following randomization) was not prohibited except as described in the protocol.
    Evidence for comparator
    		 Placebo tablets, twice daily (BID)
    Actual start date of recruitment
    30 Mar 2015
    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
    United States: 15
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Germany: 29
    Worldwide total number of subjects
    63
    EEA total number of subjects
    48
    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)
    53
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled at 4 sites in the United States, 2 sites in Germany, and 1 site each in Austria and Poland.

    Pre-assignment
    Screening details
    		 Male or female patients aged 18 years and older, who had been suffering from PN lesions involving 2 distinct anatomical areas with mean worst itch score on numerical rating scale ≥ 5.

    Period 1
    Period 1 title
    Titration period (1-2week)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nalbuphine HCl ER tablets: 90 mg BID target dose
    Arm description
    		 Nalbuphine HCl ER tablets: 90 mg BID target dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nalbuphine HCl ER tablets 90 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nalbuphine HCl ER tablets 90 mg twice daily (BID)

    Arm title
    		 Nalbuphine HCl ER tablets: 180 mg BID target dose
    Arm description
    		 Nalbuphine HCl ER tablets: 180 mg BID target dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nalbuphine HCl ER tablets 180 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nalbuphine HCl ER tablets 180 mg twice daily (BID)

    Arm title
    		 Placebo tablets
    Arm description
    		 Placebo tablets BID.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet twice daily (BID),

    Number of subjects in period 1
    		Nalbuphine HCl ER tablets: 90 mg BID target dose Nalbuphine HCl ER tablets: 180 mg BID target dose Placebo tablets
    Started
    22
    19
    22
    Completed
    22
    18
    22
    Not completed
    0
    1
    0
         randomization error
    -
    1
    -
    Period 2
    Period 2 title
    Fixed Dose Period: 8 weeks (Weeks 3 -10)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nalbuphine HCl ER tablets: 90 mg BID target dose
    Arm description
    		 Nalbuphine HCl ER tablets: 90 mg BID target dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nalbuphine HCl ER tablets 90 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nalbuphine HCl ER tablets 90 mg twice daily (BID)

    Arm title
    		 Nalbuphine HCl ER tablets: 180 mg BID target dose
    Arm description
    		 Nalbuphine HCl ER tablets: 180 mg BID target dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nalbuphine HCl ER tablets 180 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nalbuphine HCl ER tablets 180 mg twice daily (BID)

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets twice daily (BID).

    Investigational medicinal product name
    Nalbuphine HCl ER tablets 90 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Modified-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nalbuphine HCl ER tablets 90 mg twice daily (BID)

    Arm title
    		 Placebo tablets
    Arm description
    		 Placebo tablets BID.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet twice daily (BID),

    Number of subjects in period 2
    		Nalbuphine HCl ER tablets: 90 mg BID target dose Nalbuphine HCl ER tablets: 180 mg BID target dose Placebo tablets
    Started
    22
    18
    22
    Completed
    18
    12
    20
    Not completed
    4
    6
    2
         adverse events
    3
    5
    1
         Lack of efficacy
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Titration period (1-2week)
    Reporting group description
    		 -

    Reporting group values
    		 Titration period (1-2week) Total
    Number of subjects
    		 63 63
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 53 53
        From 65-84 years
    		 10 10
    Gender categorical
    Units: Subjects
        Female
    		 35 35
        Male
    		 28 28
    Subject analysis sets

    Subject analysis set title
    The MITT analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The MITT population consisted of all randomly assigned patients who provided a baseline calculated NRS and at least 1 postbaseline NRS during randomized treatment.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population will consist of all randomized patients who have received a single dose of study medication.

    Subject analysis sets values
    		 The MITT analysis set Safety Analysis Set
    Number of subjects
    62
    62
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    52
    52
        From 65-84 years
    10
    10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    34
    34
        Male
    28
    28

    End points

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    End points reporting groups
    Reporting group title
    Nalbuphine HCl ER tablets: 90 mg BID target dose
    Reporting group description
    		 Nalbuphine HCl ER tablets: 90 mg BID target dose

    Reporting group title
    Nalbuphine HCl ER tablets: 180 mg BID target dose
    Reporting group description
    		 Nalbuphine HCl ER tablets: 180 mg BID target dose

    Reporting group title
    Placebo tablets
    Reporting group description
    		 Placebo tablets BID.
    Reporting group title
    Nalbuphine HCl ER tablets: 90 mg BID target dose
    Reporting group description
    		 Nalbuphine HCl ER tablets: 90 mg BID target dose

    Reporting group title
    Nalbuphine HCl ER tablets: 180 mg BID target dose
    Reporting group description
    		 Nalbuphine HCl ER tablets: 180 mg BID target dose

    Reporting group title
    Placebo tablets
    Reporting group description
    		 Placebo tablets BID.

    Subject analysis set title
    The MITT analysis set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The MITT population consisted of all randomly assigned patients who provided a baseline calculated NRS and at least 1 postbaseline NRS during randomized treatment.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population will consist of all randomized patients who have received a single dose of study medication.

    Primary: The proportion of patients with at least a 30% reduction in the 7-day average daily

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    End point title
    		 The proportion of patients with at least a 30% reduction in the 7-day average daily
    End point description
    At least 30% reduction in 7-day worst itch intensity NRS from baseline to week 10 Modified Intent-To-Treat Population. Patients with a 30% or greater reduction in worst itch NRS from baseline will be defined as responders. Baseline is defined as the mean of the worst itch NRS scores across the 7 days prior to the baseline visit. The week 10 worst itch intensity NRS is defined as the average of the 7 consecutive days of diary data during study week 10.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 10
    End point values
    		 Nalbuphine HCl ER tablets: 90 mg BID target dose Nalbuphine HCl ER tablets: 180 mg BID target dose Placebo tablets The MITT analysis set
    Number of subjects analysed
    22
    18
    22
    62
    Units: number of subjects
        responders
    6
    9
    8
    23
        non-responders
    12
    3
    12
    27
    Statistical analysis title
    		 Statistical Analysis Plan, Final 1.0
    Comparison groups
    Nalbuphine HCl ER tablets: 180 mg BID target dose v Nalbuphine HCl ER tablets: 90 mg BID target dose v Placebo tablets
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.026 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - Statistical tests were two-sided evaluations comparing each nalbuphine HCl ER dose to placebo and were conducted at an overall 0.05 significance level using a “drop-down approach”, unless specified otherwise.
    [2] - P-value was for comparing each nalbuphine dose to placebo from a Cochran-Mantel-Haenszel test, adjusting for study site.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded starting with the signing of the first informed consent. All AEs were collected through the washout and safety follow-up visit (Visit 6) (or early termination visit).
    Adverse event reporting additional description
    The safety population consists of all randomized patients who have received a single dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 The safety population consists of all randomized patients who have received a single dose of study medication. The safety population was used in all safety analyses.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 62 (4.84%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 62 (70.97%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 62 (20.97%)
         occurrences all number
    158
    Headache
         subjects affected / exposed
    13 / 62 (20.97%)
         occurrences all number
    158
    Restless legs syndrome
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Somnolence
         subjects affected / exposed
    3 / 62 (4.84%)
         occurrences all number
    158
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 62 (11.29%)
         occurrences all number
    158
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 62 (4.84%)
         occurrences all number
    158
    Tinnitus
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    12 / 62 (19.35%)
         occurrences all number
    158
    Constipation
         subjects affected / exposed
    13 / 62 (20.97%)
         occurrences all number
    158
    Abdominal pain upper
         subjects affected / exposed
    3 / 62 (4.84%)
         occurrences all number
    158
    Toothache
         subjects affected / exposed
    3 / 62 (4.84%)
         occurrences all number
    158
    Diarrhoea
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Vomiting
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Respiratory, thoracic and mediastinal disorders
    Nasal dryness
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 62 (4.84%)
         occurrences all number
    158
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Muscle spasms
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 62 (9.68%)
         occurrences all number
    158
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 62 (3.23%)
         occurrences all number
    158

    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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