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    Clinical Trial Results:
    An Open Label Extension Study of the Safety and Anti-Pruritic Efficacy of Nalbuphine HCL ER Tablets in Hemodialysis Patients with Uremic Pruritus

    Summary
    EudraCT number
    		 2013-005626-29
    Trial protocol
    		 PL   RO  
    Global end of trial date
    24 Nov 2015

    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
    TR02ext
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02143973
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Trevi Therapeutics, Inc.
    Sponsor organisation address
    195 Church Street, 14th Floor, New Haven, Connecticut, United States, 06510
    Public contact
    Clinical Trial Information, Trevi Therapeutics, Inc., 001 203304-2499, thomas.sciascia@trevitherapeutics.com
    Scientific contact
    Clinical Trial Information, Trevi Therapeutics, Inc., 001 203304-2499, thomas.sciascia@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
    23 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives were to evaluate the safety and tolerability of nalbuphine HCl ER tablets during a drug treatment period of up to 24 weeks. The secondary objectives were to evaluate the safety of nalbuphine HCl ER tablets by achieved dose at the end of Treatment Period Week 3. The exploratory objectives are to evaluate the effect of nalbuphine HCl ER tablets on: • changes in Patient-Reported Outcome measures (NRS, Skindex-10, Itch MOS Sleep, HADS, PADS) during the Treatment Period • percentage of patients utilizing various doses of nalbuphine HCl ER tablets by Study Week • change in worst itch NRS and other PROs following a +/- 30 mg BID titration • frequency and reasons for dose up- and down-titration and treatment discontinuation during the study • changes in the PRO measurements during the Washout Period after cessation of treatment of nalbuphine HCl ER tablets • time to first use of rescue medications and the number of days of use of rescue medications for itching.
    Protection of trial subjects
    An independent Data Safety Monitoring Board (DSMB) periodically reviewed safety data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Sep 2014
    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
    Poland: 7
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    United States: 145
    Worldwide total number of subjects
    167
    EEA total number of subjects
    22
    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)
    140
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients who had successfully completed the TR02 study and wished to participate in TR02ext were enrolled, treated, and analyzed.

    Pre-assignment
    Screening details
    		 Of the three hundred seventy-three patients that were randomized to TR02, 184 subjects both completed TR02 and enrolled into TR02ext. 167 subjects who enrolled into TR02ext were exposed to nalbuphine HCl ER tablet administration and are the basis of the study safety population analysis.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Safety Population
    Arm description
    		 The nalbuphine dose was titrated based on NRS scores between Treatment Visits 1 and 3, after which time the dose achieved (30 mg QD – 120 mg BID) as of the end of Treatment Week 3 was maintained up to an additional 21 weeks. At the end of the titration period at week 3 of the Treatment Period the distribution of dosing was 14 subjects (8.4%) at 30 mg BID, 35 subjects (21%) at 60 mg BID, 30 subjects (18%) at 90 mg BID and 70 subjects (41.9%) at 120 mg BID. 8 subjects (4.8%) were missing data. Analyzing the distribution of study drug use over the course of the study shows that 120 mg BID was the most frequent dose used by patients followed by the 60 BID dose.
    Arm type
    		 Treatment

    Investigational medicinal product name
    nalbuphine hydrochloride (HCl) extended-release (ER) tablets
    Investigational medicinal product code
    Nalbuphine HCl ER
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg QD – 120 mg BID, Oral use

    Number of subjects in period 1
    		Safety Population
    Started
    167
    Completed
    101
    Not completed
    66
         Consent withdrawn by subject
    18
         Adverse event, non-fatal
    19
         Death
    4
         Other
    15
         Pregnancy
    1
         Renal transplantation
    3
         patients non-compliance with protocol
    5
         Lack of efficacy
    1
    Period 2
    Period 2 title
    Observation Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 No drug treatment
    Arm description
    		 While patients remained in the Observation Period, they were not considered enrolled into the study, but as participating in an extended screening process until they were eligible for treatment.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		No drug treatment
    Started
    101
    Completed
    101
    Period 3
    Period 3 title
    Washout and Safety Follow-Up Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 No treatment
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		No treatment
    Started
    101
    Completed
    101

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 The nalbuphine dose was titrated based on NRS scores between Treatment Visits 1 and 3, after which time the dose achieved (30 mg QD – 120 mg BID) as of the end of Treatment Week 3 was maintained up to an additional 21 weeks. At the end of the titration period at week 3 of the Treatment Period the distribution of dosing was 14 subjects (8.4%) at 30 mg BID, 35 subjects (21%) at 60 mg BID, 30 subjects (18%) at 90 mg BID and 70 subjects (41.9%) at 120 mg BID. 8 subjects (4.8%) were missing data. Analyzing the distribution of study drug use over the course of the study shows that 120 mg BID was the most frequent dose used by patients followed by the 60 BID dose.

    Reporting group values
    		 Safety Population Total
    Number of subjects
    		 167 167
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 140 140
        From 65-84 years
    		 27 27
    Age continuous
    Units: years
        median (standard deviation)
    		 53 ± 12.2 -
    Gender categorical
    Units: Subjects
        Female
    		 92 92
        Male
    		 75 75

    End points

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    End points reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 The nalbuphine dose was titrated based on NRS scores between Treatment Visits 1 and 3, after which time the dose achieved (30 mg QD – 120 mg BID) as of the end of Treatment Week 3 was maintained up to an additional 21 weeks. At the end of the titration period at week 3 of the Treatment Period the distribution of dosing was 14 subjects (8.4%) at 30 mg BID, 35 subjects (21%) at 60 mg BID, 30 subjects (18%) at 90 mg BID and 70 subjects (41.9%) at 120 mg BID. 8 subjects (4.8%) were missing data. Analyzing the distribution of study drug use over the course of the study shows that 120 mg BID was the most frequent dose used by patients followed by the 60 BID dose.
    Reporting group title
    No drug treatment
    Reporting group description
    		 While patients remained in the Observation Period, they were not considered enrolled into the study, but as participating in an extended screening process until they were eligible for treatment.
    Reporting group title
    No treatment
    Reporting group description
    		 -

    Primary: overall incidence and nature of Treatment-Emergent AEs (TEAES)

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    End point title
    		 overall incidence and nature of Treatment-Emergent AEs (TEAES) [1]
    End point description
    The primary endpoint of the study was a description of the overall incidence and nature of Treatment-Emergent AEs (TEAES). Overall, 131 patients (78.4%) of the safety population (n=167) experienced at least 1 TEAE. Of these, study drug-related TEAEs were reported in 64 patients (38.3%). 51 patients (30.5%) of the safety population experienced at least 1 treatment-emergent SAE.
    End point type
    Primary
    End point timeframe
    TEAEs occurring in the Safety Population (all patients in the TR02ext study).
    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: No analysis was performer as this was a single-arm, open-label, observational study.
    End point values
    		 Safety Population
    Number of subjects analysed
    167
    Units: number of events
    607
    No statistical analyses for this end point

    Secondary: Worst itch Numerical Rating Scale (NRS)

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    End point title
    		 Worst itch Numerical Rating Scale (NRS)
    End point description
    Mean worst itch was decreased from baseline to the end of treatment. No formal statistical testing has been conducted.
    End point type
    Secondary
    End point timeframe
    All patients with a baseline and at least one post-baseline value for an efficacy assessment were included in the summary of the change from baseline for that efficacy endpoint.
    End point values
    		 Safety Population
    Number of subjects analysed
    102
    Units: scales
        arithmetic mean (standard deviation)
    -2.7 ± 2.69
    No statistical analyses for this end point

    Secondary: Skindex-10

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    End point title
    		 Skindex-10
    End point description
    Mean Skindex-10 decreased from baseline to all measured time points in the safety population. The decrease in mean Skindex-10 was most pronounced in the subgroup of patients with baseline NRS values of ≥ 7. No statistical analyses for this end point.
    End point type
    Secondary
    End point timeframe
    All patients with a baseline and at least one post-baseline value for an efficacy assessment were included in the summary of the change from baseline for that efficacy endpoint.
    End point values
    		 Safety Population
    Number of subjects analysed
    102
    Units: scales
        arithmetic mean (standard deviation)
    -10.56 ± 14.24
    No statistical analyses for this end point

    Secondary: Patient Assessed Disease Severity Scale (PADS)

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    End point title
    		 Patient Assessed Disease Severity Scale (PADS)
    End point description
    There was a shift in PADS scores in subjects evaluated in the End of Treatment Visit in the direction of more subjects with PADs “A” scores and fewer subjects with PADS “B” and “C” scores. Of the 167 subjects in the safety population, 99 subjects completed an End of Treatment Visit. Of the 99 these subjects, 17/99 (17%) were classified by the PADS as “A”; 61/99 (62%) were classified as “B” and 21/99 (21%) were classified as “C” patients at TR02ext baseline. At the End of Treatment Visit, the distribution of the PADS scores among those 99 subjects were: 44/99 (44%) PADS “A”; 46/99 (46%) PADS “B” and 9/99 (9%) PADS “C”. 99 (8%) subjects shifted from PADS “A” to PADS “B” or from PADS “A” or PADS “B” to PADS “C”. No statistical analyses for this end point.
    End point type
    Secondary
    End point timeframe
    All patients with a baseline and at least one post-baseline value for an efficacy assessment were included in the summary of the change from baseline for that efficacy endpoint.
    End point values
    		 Safety Population
    Number of subjects analysed
    99
    Units: percentages
    8
    No statistical analyses for this end point

    Secondary: Itch MOS Sleep Scale

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    End point title
    		 Itch MOS Sleep Scale
    End point description
    Mean Itch MOS decreased from baseline to the end of treatment. No statistical analyses for this end point.
    End point type
    Secondary
    End point timeframe
    All patients with a baseline and at least one post-baseline value for an efficacy assessment were included in the summary of the change from baseline for that efficacy endpoint.
    End point values
    		 Safety Population
    Number of subjects analysed
    102
    Units: scales
        arithmetic mean (standard deviation)
    -8.75 ± 16.28
    No statistical analyses for this end point

    Secondary: Hospital Anxiety and Depression Scale (HADS) - depression

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    End point title
    		 Hospital Anxiety and Depression Scale (HADS) - depression
    End point description
    Mean HADS Depression Subscale and Mean HADS Anxiety Subscale had decreased between the baseline and End of Treatment visits in the safety population. The decrease in mean HADS Depression and HADS Anxiety subscales were most pronounced in the subgroup of patients with baseline NRS values of ≥ 7. No statistical analyses for this end point.
    End point type
    Secondary
    End point timeframe
    All patients with a baseline and at least one post-baseline value for an efficacy assessment were included in the summary of the change from baseline for that efficacy endpoint.
    End point values
    		 Safety Population
    Number of subjects analysed
    101
    Units: scales
        arithmetic mean (standard deviation)
    -1.15 ± 3.29
    No statistical analyses for this end point

    Secondary: Use of rescue medications

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    End point title
    		 Use of rescue medications
    End point description
    Less than 1/3 of the safety population recorded the use of protocol specified rescue medication during the study. No statistical analyses for this end point.
    End point type
    Secondary
    End point timeframe
    All patients with a baseline and at least one post-baseline value for an efficacy assessment were included in the summary of the change from baseline for that efficacy endpoint.
    End point values
    		 Safety Population
    Number of subjects analysed
    167
    Units: days
        arithmetic mean (standard deviation)
    14 ± 39.3
    No statistical analyses for this end point

    Secondary: Hospital Anxiety and Depression Scale (HADS) - anxiety

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    End point title
    		 Hospital Anxiety and Depression Scale (HADS) - anxiety
    End point description
    Mean HADS Depression Subscale and Mean HADS Anxiety Subscale had decreased between the baseline and End of Treatment visits in the safety population No statistical analyses for this end point.
    End point type
    Secondary
    End point timeframe
    All patients with a baseline and at least one post-baseline value for an efficacy assessment were included in the summary of the change from baseline for that efficacy endpoint.
    End point values
    		 Safety Population
    Number of subjects analysed
    101
    Units: scales
        arithmetic mean (standard deviation)
    -1.16 ± 3.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were continuously evaluated throughout the study.
    Adverse event reporting additional description
    Overall, 133 patients (79.6%) of the safety population (n=167) experienced at least 1 TEAE. Of these, study drug-related TEAEs were reported in 64 patients (38.3%). 54 patients (32.3%) of the safety population experienced at least 1 treatment-emergent SAE. The majority of TEAEs were grade 1 (41.6%) or grade 2 (42.5%) in intensity.
    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 nalbuphine dose was titrated based on NRS scores between Treatment Visits 1 and 3, after which time the dose achieved (30 mg QD – 120 mg BID) as of the end of Treatment Week 3 was maintained up to an additional 21 weeks. At the end of the titration period at week 3 of the Treatment Period the distribution of dosing was 14 subjects (8.4%) at 30 mg BID, 35 subjects (21%) at 60 mg BID, 30 subjects (18%) at 90 mg BID and 70 subjects (41.9%) at 120 mg BID. 8 subjects (4.8%) were missing data. Analyzing the distribution of study drug use over the course of the study shows that 120 mg BID was the most frequent dose used by patients followed by the 60 BID dose.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Non-serious Adverse Events were not reported out in a separate and distinct data listing for this trial. The number of subject experiencing non-serious adverse events is 79 based on the following: Safety population = 167 Subjects experiencing no TEAE = 34 Subjects with TEAE = 133 Subjects with serious TEAE = 54.
    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 167 (32.34%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 167 (3.59%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Anticoagulation drug level below therapeutic
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arteriovenous graft site haemorrhage
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dialysis related complication
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular graft complication
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Arteriovenous graft site infection
         subjects affected / exposed
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neck abscess
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 167 (0.60%)
         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
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 167 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2014
    Clinical research Protocol TR02ext v2.0 was produced for the following purposes: • Update the Phase of the study from Phase 2 to a Phase 2/3. • Correction made to sample Numerical Rating Scale included in Appendix 4. • Correction to the EudraCT number on the cover page • To incorporate clarifications, administrative changes and correction of typographical errors throughout the protocol.
    19 Mar 2015
    Clinical research Protocol TR02ext v3.0 was produced for the following purposes: • To add Failure-to-Improve criteria • To add a Data Safety Monitoring Board (DSMB) • To add central cardiac core laboratory read of study ECGs • To provide clarity in the transition of patients from the observation period to the treatment period • To include gender related PK and AE information from previous studies • To include summary language from the Investigator Brochure (IB) related to most frequently reported adverse events from previous studies • To provide clarity on the titration schedule and dose adjustment processes • To provide clarity on the start of AE data capture • To incorporate EU directives • To incorporate clarifications, administrative changes and correction of typographical errors throughout the protocol.
    14 May 2015
    Clinical research Protocol TR02ext v4.0 was produced for the following purposes: • To incorporate clarifications, administrative changes and correction of typographical errors throughout the protocol.

    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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