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    Clinical Trial Results:
    Prospective, single-blind, placebo-controlled, three-treatment, three-period, adaptive multi-centre Phase IIa (proof-of-concept) trial to investigate the efficacy, safety, and tolerability of Ketamine HCl PR tablets in patients with chronic non-malignant neuropathic pain

    Summary
    EudraCT number
    		 2014-004535-40
    Trial protocol
    		 HU   DE  
    Global end of trial date
    31 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2020
    First version publication date
    10 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0189/DEV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Develco Pharma Schweiz AG
    Sponsor organisation address
    Hohenrainstr. 12 D, Pratteln, Switzerland, 4133
    Public contact
    Clinical Trial Manager, Develco Pharma Schweiz AG, 0041 614255020, k.schmid@develco.ch
    Scientific contact
    Clinical Trial Manager, Develco Pharma Schweiz AG, 0041 614255020, k.schmid@develco.ch
    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 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of Ketamine HCl PR tablets administered twice daily as add-on therapy to the individual standard treatment regimen of each patient in comparison to placebo in the relief of chronic non-malignant neuropathic pain as determined by absolute changes in the “current” pain intensity (PI) score on the visual analogue scale (VAS)
    Protection of trial subjects
    Due to the prolonged release formulation used in this study the risks and frequencies of adverse reactionswere extected to be remarkably lower and with milder severities as compared to formulations for injection. These risks were further minimised by regular contact between the patient and investigator and by close safety monitoring.
    Background therapy
    		 The patients continued their previous individual standard medication and regimen for the treatment of pain.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 May 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
    Germany: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    43
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients ≥18 years of age with a documented history of chronic non-malignant neuropathic pain and with inadequate pain control

    Pre-assignment
    Screening details
    		 A total of 70 subjects were screened. 16 subjects were screening failures.

    Pre-assignment period milestones
    Number of subjects started
    		 70 [1]
    Number of subjects completed
    		 54

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Other: 15
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled in the trial is the number of subjects assigned to treatment.
    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Overall - Low
    Arm description
    		 Individual standard treatment of pain plus Ketamine HCl PR twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine HCl PR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Period 1: Ketamine HCl PR Placebo tablets, one tablet twice daily Period 2 : Ketamine HCl 40 mg PR tablets, one tablet twice daily (TDD: 80 mg) Period 3: Ketamine HCl 80 mg PR tablets, one tablet twice daily (TDD: 160 mg)

    Arm title
    		 Overall - High
    Arm description
    		 Individual standard treatment of pain plus Ketamine HCl PR twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketamine HCl PR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Period 1: Ketamine HCl PR Placebo tablets, one tablet twice daily Period 2 : Ketamine HCl 40+60 mg PR tablets, two tablets twice daily (TDD: 240 mg) Period 3: Ketamine HCl 80 mg PR tablets, two tablets twice daily (TDD: 320 mg)

    Number of subjects in period 1
    		Overall - Low Overall - High
    Started
    25
    29
    Completed
    23
    25
    Not completed
    2
    4
         Adverse event, non-fatal
    -
    2
         Other
    2
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall - Low
    Reporting group description
    		 Individual standard treatment of pain plus Ketamine HCl PR twice daily

    Reporting group title
    Overall - High
    Reporting group description
    		 Individual standard treatment of pain plus Ketamine HCl PR twice daily

    Reporting group values
    		 Overall - Low Overall - High Total
    Number of subjects
    		 25 29 54
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    		 0 0 0
        Preterm newborn- gestational age < 37 wk
    		 0 0 0
        Newborns (0-27days)
    		 0 0 0
        Infants and toddlers (28days – 23months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 year)
    		 0 0 0
        From 18 - 64 years
    		 18 25 43
        From 65 – 84 years
    		 7 4 11
        Over 85 years
    		 0 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    		 52.8 ( 15.46 ) 52.9 ( 12.51 ) -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 15 17 32
        Male
    		 10 12 22

    End points

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    End points reporting groups
    Reporting group title
    Overall - Low
    Reporting group description
    		 Individual standard treatment of pain plus Ketamine HCl PR twice daily

    Reporting group title
    Overall - High
    Reporting group description
    		 Individual standard treatment of pain plus Ketamine HCl PR twice daily

    Subject analysis set title
    Overall - Low x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of IMP.

    Subject analysis set title
    Overall - High x Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of IMP.

    Subject analysis set title
    Overall - Low x FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received at least one dose of Ketamine HCl PR tablets and with at least one current pain intensity assessment during Period 2 of the single-blind treatment phase.

    Subject analysis set title
    Overall - High x FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received at least one dose of Ketamine HCl PR tablets and with at least one current pain intensity assessment during Period 2 of the single-blind treatment phase.

    Primary: Mean current PI change

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    End point title
    		 Mean current PI change
    End point description
    Absolute change from baseline in current PI on 0 - 100 mm VAS (mean of all current PIs of the last four days of each treatment period) after Ketamine HCl PR Placebo tablets versus Ketamine HCl PR tablets.
    End point type
    Primary
    End point timeframe
    Baseline up to three weeks in single-blind treatment phase
    End point values
    		 Overall - Low x FAS Overall - High x FAS
    Number of subjects analysed
    23
    27
    Units: mm
    number (standard deviation)
        mm
    23
    26
    Statistical analysis title
    		 Statistical Analysis of mean current PI change
    Statistical analysis description
    Absolute changes in mean current PI scores are analysed via a mixed model for repeated measures (MMRM) with baseline mean current PI as a covariate, period and stage as a fixed factors and stage-by-period interaction
    Comparison groups
    Overall - Low x FAS v Overall - High x FAS
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1547 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -4.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.4
         upper limit
    		 1.7
    Notes
    [1] - Overall - High x FAS Period 3 - Period 1
    Statistical analysis title
    		 Statistical Analysis of mean current PI change
    Statistical analysis description
    Absolute changes in mean current PI scores are analysed via a mixed model for repeated measures (MMRM) with baseline mean current PI as a covariate, period and stage as a fixed factors and stage-by-period interaction
    Comparison groups
    Overall - Low x FAS v Overall - High x FAS
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0034 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -9.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.41
         upper limit
    		 -3.45
    Notes
    [2] - Overall - Low x FAS Period 3 - Period 1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first intake of IMP and not more than 14 days after last administration of IMP
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Overall - High x Safety
    Reporting group description
    		 Subjects in the Safety set treated with Placebo

    Reporting group title
    Overall - Low x Safety
    Reporting group description
    		 Subjects in the Safety set treated with Low

    Serious adverse events
    		 Overall - High x Safety Overall - Low x Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall - High x Safety Overall - Low x Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 29 (51.72%)
    12 / 25 (48.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 25 (12.00%)
         occurrences all number
    1
    4
    Pain
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Sleep Disorder
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Hepatic Enzyme Increased
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 25 (4.00%)
         occurrences all number
    4
    1
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Biopsy Peripheral Nerve
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Blood Pressure Increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Heart Rate Increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Transaminases Increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 29 (20.69%)
    1 / 25 (4.00%)
         occurrences all number
    7
    1
    Headache
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 25 (4.00%)
         occurrences all number
    4
    1
    Tension Headache
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 25 (8.00%)
         occurrences all number
    3
    2
    Constipation
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    Abdominal Pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Dry Mouth
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Rash Pruritic
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    Limb Discomfort
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    Bronchitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2015
    Global Protocol Amendment No. 1 This protocol amendment provides the IMP dose specification for Stage 2 of the 0189/DEV trial outlined in Protocol Final Version 1.0 (21-JAN-2015)

    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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