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    Clinical Trial Results:
    A randomized, controlled, long-term safety study evaluating the effect of repeated applications of Qutenza (Capsaicin (8%) high-concentration patch) plus Standard of Care versus Standard of Care Alone in participants with Painful Diabetic Peripheral Neuropathy (PDPN).

    Summary
    EudraCT number
    2009-016458-42
    Trial protocol
    DE   BE   GB   CZ   NL   ES   IT   PL  
    Global end of trial date
    27 Feb 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Jun 2016
    First version publication date
    05 Jun 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of full data set = Revisions to the data made and clarification of previously reported data provided.

    Trial information

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    Trial identification
    Sponsor protocol code
    E05-CL-3002/PACE
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01478607
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe B.V.
    Sponsor organisation address
    Sylviusweg 62, 2333 BE Leiden, Netherlands,
    Public contact
    Medical Science Director, Global Medical Science Astellas Pharma Global Development, Astellas Pharma Europe B.V., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Medical Science Director, Global Medical Science Astellas Pharma Global Development, Astellas Pharma Europe B.V., Astellas.resultsdisclosure@astellas.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
    27 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to assess safety and efficacy of repeat applications of Qutenza (Capsaicin (8%) high-concentration patch) administered over a period of 12 months in subjects with Painful Diabetic Peripheral Neuropathy (PDPN).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    Participants received topical anaesthetic, Eutectic Mixture of Local Anesthetics (EMLA), on their painful affected area(s) prior to placement of Qutenza patches (Capsaicin (8%) high-concentration patch). A short-acting analgesic (including short-acting opioid if required) could be administered to relieve treatment-associated discomfort during treatment procedure and up to 5 consecutive days post-treatment. Any pain medications used as Standard of Care (SOC) in Painful Diabetic Peripheral Neuropathy (PDPN) were used as per the investigator’s discretion. Furthermore participants were allowed to take aspirin up to 325 mg/day for the prevention of ischemia as well as any anti-diabetic medication (including insulin and OHA) and any other medical therapy not specifically prohibited (e.g., statins, fibric acid derivatives etc.). Participants could receive oral and transdermal opioid medication if it did not exceed a total oral daily dose of morphine of 80 mg or the equivalent, which was to be calculated using the Opioid Dose Worksheet. Any changes, additions or discontinuations to medications were assessed and recorded at every study visit. Cooling measures, such as cool packs, a light wrapping of gauze misted with cool water or a fan were permitted only after patch removal.
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Nov 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
    Poland: 81
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Czech Republic: 100
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Russian Federation: 92
    Country: Number of subjects enrolled
    Ukraine: 111
    Worldwide total number of subjects
    468
    EEA total number of subjects
    265
    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)
    308
    From 65 to 84 years
    160
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This randomized, controlled, long-term safety study was conducted at 71 centers in a total of 11 countries. If the results of the screening assessments did not reveal any conditions inconsistent with the inclusion and exclusion criteria, the patient qualified for enrollment.

    Pre-assignment
    Screening details
    After obtaining written informed consent, screening assessments were performed including the collection of demographics,medical history,physical examination,vital signs, electrocardiogram (ECG), pregnancy test,identification and assessment of painful areas, and questions of the Brief Pain Inventory-Diabetic Peripheral Neuropathy (BPI-DN).

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Assessor [1]
    Blinding implementation details
    Patients and investigators were not blinded but physicians assessing neurological function were blinded to treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC
    Arm description
    Qutenza is a high-concentration (8%) capsaicin patch applied for 30 minutes.The efficacy of a single 30-minute treatment has been demonstrated in patients with HIV-Associated Neuropathy (HIV-AN). The rationale for the 30-minute application time was to keep the mode of administration of the investigational medicinal product (Qutenza) in full accordance with the approved Summary of Product Characteristics(SmPC) for application time to the feet.
    Arm type
    Experimental

    Investigational medicinal product name
    Qutenza (Capsaicin (8%) high-concentration patch)
    Investigational medicinal product code
    A0805/NGX-4010
    Other name
    Pharmaceutical forms
    Cutaneous patch
    Routes of administration
    Topical use
    Dosage and administration details
    Each patch contained a total of 179 mg capsaicin or 640 μg of capsaicin per 1 cm2 of patch (8% w/w). Up to 4 patches (1120 cm2) could be applied at each application. Qutenza is a topical capsaicin delivery system in the form of a patch which had to be applied to intact, nonirritated dry skin. The patches were applied for 30 minutes (arm 1) or 60 minutes (arm 2) to painful areas.

    Arm title
    Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Arm description
    Qutenza is a high-concentration (8%) capsaicin patch applied for 60 minutes. The efficacy of a single 60 minute treatment has been demonstrated in Postherpetic Neuralgia (PHN).The rationale for studying the effects of a 60-minute application time in this study was to cover the contingency that this may ultimately prove to be the optimal application time for efficacy in patients with Painful Diabetic Peripheral Neuropathy (PDPN).
    Arm type
    Experimental

    Investigational medicinal product name
    Qutenza (Capsaicin (8%) high-concentration patch)
    Investigational medicinal product code
    A0805/NGX-4010
    Other name
    Pharmaceutical forms
    Cutaneous patch
    Routes of administration
    Topical use
    Dosage and administration details
    Each patch contained a total of 179 mg capsaicin or 640 μg of capsaicin per 1 cm^2 of patch (8% w/w). Up to 4 patches (1120 cm^2) could be applied at each application. Qutenza is a topical Capsaicin patch which had to be applied to intact, non-irritated, dry skin. The patches were applied for 30 minutes (arm 1) or 60 minutes (arm 2) to painful areas.

    Arm title
    SOC (Standard of Care)
    Arm description
    Control Group-Standard of Care
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Patients and investigators were not blinded but physicians assessing neurological function were blinded to treatment.
    Number of subjects in period 1
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Started
    156
    157
    155
    Completed
    132
    128
    128
    Not completed
    24
    29
    27
         Protocol deviation
    1
    3
    3
         Lack of efficacy
    3
    1
    -
         Due to personal problems can't attend study visits
    1
    1
    1
         Adverse event, non-fatal
    7
    8
    3
         Consent withdrawn by subject
    10
    15
    19
         Lost to follow-up
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC
    Reporting group description
    Qutenza is a high-concentration (8%) capsaicin patch applied for 30 minutes.The efficacy of a single 30-minute treatment has been demonstrated in patients with HIV-Associated Neuropathy (HIV-AN). The rationale for the 30-minute application time was to keep the mode of administration of the investigational medicinal product (Qutenza) in full accordance with the approved Summary of Product Characteristics(SmPC) for application time to the feet.

    Reporting group title
    Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Reporting group description
    Qutenza is a high-concentration (8%) capsaicin patch applied for 60 minutes. The efficacy of a single 60 minute treatment has been demonstrated in Postherpetic Neuralgia (PHN).The rationale for studying the effects of a 60-minute application time in this study was to cover the contingency that this may ultimately prove to be the optimal application time for efficacy in patients with Painful Diabetic Peripheral Neuropathy (PDPN).

    Reporting group title
    SOC (Standard of Care)
    Reporting group description
    Control Group-Standard of Care

    Reporting group values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care) Total
    Number of subjects
    156 157 155 468
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    98 100 110 308
        From 65-84 years
    58 57 45 160
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.9 ± 10.88 61 ± 10.3 59.1 ± 10.32 -
    Gender categorical
    Units: Subjects
        Female
    82 78 84 244
        Male
    74 79 71 224
    Race
    Units: Subjects
        White
    154 155 154 463
        Other
    2 2 1 5
    Age group summary by treatment group
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    98 100 110 308
        From 65-84 years
    58 57 45 160
        85 years and over
    0 0 0 0
    Country summary by treatment group
    Units: Subjects
        Belgium
    2 3 2 7
        Czech Republic
    32 33 35 100
        France
    5 4 2 11
        Germany
    16 9 14 39
        Italy
    2 2 1 5
        Netherlands
    4 6 5 15
        Poland
    27 29 25 81
        Russian Federation
    29 31 32 92
        Spain
    0 0 1 1
        Ukraine
    36 39 36 111
        United Kingdom
    3 1 2 6
    Duration of PDPN (years)
    Units: year
        arithmetic mean (standard deviation)
    4.1 ± 3.68 4.4 ± 3.86 4.4 ± 3.61 -
    HbA1c (mmol/mol) (Screening)
    Units: (mmol/mol)
        arithmetic mean (standard deviation)
    56.561 ± 10.7651 57.497 ± 10.7887 57.575 ± 11.3553 -
    Screening BPI-DN Scores, Pain on the Average (Question 5 )
    Units: Number
        arithmetic mean (standard deviation)
    5.6 ± 1.27 5.6 ± 1.4 5.7 ± 1.3 -

    End points

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    End points reporting groups
    Reporting group title
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC
    Reporting group description
    Qutenza is a high-concentration (8%) capsaicin patch applied for 30 minutes.The efficacy of a single 30-minute treatment has been demonstrated in patients with HIV-Associated Neuropathy (HIV-AN). The rationale for the 30-minute application time was to keep the mode of administration of the investigational medicinal product (Qutenza) in full accordance with the approved Summary of Product Characteristics(SmPC) for application time to the feet.

    Reporting group title
    Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Reporting group description
    Qutenza is a high-concentration (8%) capsaicin patch applied for 60 minutes. The efficacy of a single 60 minute treatment has been demonstrated in Postherpetic Neuralgia (PHN).The rationale for studying the effects of a 60-minute application time in this study was to cover the contingency that this may ultimately prove to be the optimal application time for efficacy in patients with Painful Diabetic Peripheral Neuropathy (PDPN).

    Reporting group title
    SOC (Standard of Care)
    Reporting group description
    Control Group-Standard of Care

    Primary: Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy (QOL-DN) from Baseline to End of Study (EOS)(SAF)

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    End point title
    Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy (QOL-DN) from Baseline to End of Study (EOS)(SAF)
    End point description
    The endpoint assessed percentage change from baseline to end of study (EOS) in Norfolk Quality of Life (QOL)-Diabetic Neuropathy (DN) total score. The Norfolk (QOL-DN) is a self-administered questionnaire, designed to capture and quantify the impact of DN on the quality of life of individual participants. In general, items 1 to 7 (Part I) are a simple inventory of neuropathy symptoms. The presence of the symptom is checked and an absence of a symptom is checked under “none.” Positive responses are scored as 1 and negative responses as 0. Reduction in score means improvement in QOL. Items 8 to 35 (Part II) pertain to Activities of Daily Life, and most of these are scored on a 5-point Likert scale ranging from 0 (“Not a problem” or “Not at all”) to 4 (“Severe problem” or “Severely”). The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Primary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    134
    139
    123
    Units: Number of Participants
        arithmetic mean (standard deviation)
    -27.6 ± 49.95
    -32.8 ± 53.21
    -6.7 ± 54.12
    Statistical analysis title
    Norfolk QOL-DN - Qutenza 30 min versus SOC
    Statistical analysis description
    Pairwise comparison with SOC alone using a one-way ANOVA with treatment group as fixed effect.
    Comparison groups
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC v SOC (Standard of Care)
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    LS mean difference
    Point estimate
    -20.9
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -31.7
         upper limit
    -10.1
    Notes
    [1] - One way ANOVA analysis was used with Last Observation Carried Forward (LOCF) imputation.
    Statistical analysis title
    Norfolk QOL-DN - Qutenza 60 min versus SOC
    Statistical analysis description
    Pairwise comparison with SOC alone using a one-way ANOVA with treatment group as fixed effect.
    Comparison groups
    SOC (Standard of Care) v Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    LS mean difference
    Point estimate
    -26.1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -36.8
         upper limit
    -15.4
    Notes
    [2] - One way ANOVA analysis was used with Last Observation Carried Forward (LOCF) imputation.

    Secondary: Utah Early Neuropathy Scale (UENS) used to detect and quantify early neuropathy and changes in sensory severity (SAF)

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    End point title
    Utah Early Neuropathy Scale (UENS) used to detect and quantify early neuropathy and changes in sensory severity (SAF)
    End point description
    The Utah Early Neuropathy Scale (UENS) is a sensitive clinical examination scale which was specifically developed to detect changes or progression in the severity and anatomical distribution of sensory neuropathy. The UENS places most emphasis on the severity and anatomical distribution of sharp sensation in the lower limbs. A reduction in the UENS score indicates a lack of deterioration in neurological function including no increase in small-fiber sensory loss. The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    149
    153
    142
    Units: Number of Participants
        arithmetic mean (standard deviation)
    -2.1 ± 5.03
    -3 ± 5.05
    -1.2 ± 4.22
    Statistical analysis title
    UENS Qutenza 30 minutes versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in UENS Total Score. Statistical analysis was done with one-way ANOVA and Last Observation Carried Forward (LOCF) imputation.
    Comparison groups
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC v SOC (Standard of Care)
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.9
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    0.1
    Statistical analysis title
    UENS Qutenza 60 minutes versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in UENS total score. Statistical analysis was done with one-way ANOVA and Last Observation Carried Forward (LOCF) imputation.
    Comparison groups
    SOC (Standard of Care) v Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS mean difference
    Point estimate
    -1.7
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    -0.8

    Secondary: Tolerability of patch application by dermal assessment (SAF)

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    End point title
    Tolerability of patch application by dermal assessment (SAF) [3]
    End point description
    Dermal assessment at patch applications was assessed 15 and 60 minutes after the patch removal and according to categories, Category=0 (No evidence of irritation), Category=1 (Minimal erythema barely perceptive), Category=2(Definite erythema, readily visible; minimal edema or minimal papular response), Category=3 (Erythema and papules), Category=4 (Definite edema), Category=5 (Erythema, edema, and papules), Category=6 (Vesicular eruption), Category=7 (Strong reaction spreading beyond test site) and combined category >= 4 (Definite edema or higher).Dermal assessments were performed on a 0 to 7 point severity scale at screening, and before and after patch application. The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Standard of Care (SOC) arm was not reported in the Clinical Study Report.
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects analysed
    156
    157
    Units: Number
    number (not applicable)
        1st before EMLA Category=0[N=156;N=157]
    148
    149
        1st before EMLA Category=1[N=156;N=157]
    7
    6
        1st before EMLA Category=2[N=156;N=157]
    1
    2
        1st before EMLA Category=3[N=156;N=157]
    0
    0
        1st before EMLA Category=4[N=156;N=157]
    0
    0
        1st before EMLA Category=5[N=156;N=157]
    0
    0
        1st before EMLA Category=6[N=156;N=157]
    0
    0
        1st before EMLA Category=7[N=156;N=157]
    0
    0
        1st before EMLA CombinedCategory[N=156;N;157]
    0
    0
        1st 15 min after patch Category=0[N=156;N=157]
    106
    88
        1st 15 min after patch Category=1 [N=156;N=157]
    45
    53
        1st 15 min after patch Category=2 [N=156;N=157]
    5
    13
        1st 15 min after patch Category=3 [N=156;N=157]
    0
    3
        1st 15 min after patch Category=4 [N=156;N=157]
    0
    0
        1st 15 min after patch Category=5 [N=156;N=157]
    0
    0
        1st 15 min after patch Category=6 [N=156;N=157]
    0
    0
        1st 15 min after patch Category=7 [N=156;N=157]
    0
    0
        1st15 min after patch CombineCategory[N=156;N=157]
    0
    0
        1st 60min after patch Category=0[N=156;N=157]
    112
    95
        1st 60min after patch Category=1[N=156;N=157]
    39
    47
        1st 60min after patch Category=2[N=156;N=157]
    4
    14
        1st 60min after patch Category=3[N=156;N=157]
    1
    1
        1st 60min after patch Category=4[N=156;N=157]
    0
    0
        1st 60min after patch Category=5[N=156;N=157]
    0
    0
        1st 60min after patch Category=6[N=156;N=157]
    0
    0
        1st 60min after patch Category=7[N=156;N=157]
    0
    0
        1st 60min after patch CombineCategory[N=156;N=157]
    0
    0
        2nd before EMLA Category=0[N=148;151]
    144
    145
        2nd before EMLA Category=1[N=148;151]
    4
    5
        2nd before EMLA Category=2[N=148;151]
    0
    1
        2nd before EMLA Category=3[N=148;151]
    0
    0
        2nd before EMLA Category=4[N=148;151]
    0
    0
        2nd before EMLA Category=5[N=148;151]
    0
    0
        2nd before EMLA Category=6[N=148;151]
    0
    0
        2nd before EMLA Category=7[N=148;151]
    0
    0
        2nd before EMLA CombinedCategory[N=148;151]
    0
    0
        2nd 15min after patch Category=0[N=149;N=151]
    105
    88
        2nd 15min after patch Category=1[N=149;N=151]
    41
    53
        2nd 15min after patch Category=2[N=156;N=157]
    3
    10
        2nd 15min after patch Category=3[N=149;N=151]
    0
    0
        2nd 15min after patch Category=4[N=149;N=151]
    0
    0
        2nd 15min after patch Category=5[N=149;N=151]
    0
    0
        2nd 15min after patch Category=6[N=149;N=151]
    0
    0
        2nd 15min after patch Category=7[N=149;N=151]
    0
    0
        2nd 15min after patch CombineCategory[N=149;N=151]
    0
    0
        2nd 60min after patch Category=0[N=149;N=151]
    114
    104
        2nd 60min after patch Category=1[N=149;N=151]
    30
    38
        2nd 60min after patch Category=2[N=149;N=151]
    5
    9
        2nd 60min after patch Category=3[N=149;N=151]
    0
    0
        2nd 60min after patch Category=4[N=149;N=151]
    0
    0
        2nd 60min after patch Category=5[N=149;N=151]
    0
    0
        2nd 60min after patch Category=6[N=149;N=151]
    0
    0
        2nd 60min after patch Category=7[N=149;N=151]
    0
    0
        2nd 60min after patch CombineCategory[N=149;N=151]
    0
    0
        3rd before EMLA Category=0[N=144;N=138]
    139
    136
        3rd before EMLA Category=1[N=144;N=138]
    5
    2
        3rd before EMLA Category=2[N=144;N=138]
    0
    0
        3rd before EMLA Category=3[N=144;N=138]
    0
    0
        3rd before EMLA Category=4[N=144;N=138]
    0
    0
        3rd before EMLA Category=5[N=144;N=138]
    0
    0
        3rd before EMLA Category=6[N=144;N=138]
    0
    0
        3rd before EMLA Category=7[N=144;N=138]
    0
    0
        3rd before EMLA CombinedCategory[N=144;N=138]
    0
    0
        3rd 15min after patch Category=0[N=144;N=139]
    97
    91
        3rd 15min after patch Category=1[N=144;N=139]
    45
    41
        3rd 15min after patch Category=2[N=144;N=139]
    2
    7
        3rd 15min after patch Category=3[N=144;N=139]
    0
    0
        3rd 15min after patch Category=4[N=144;N=139]
    0
    0
        3rd 15min after patch Category=5[N=144;N=139]
    0
    0
        3rd 15min after patch Category=6[N=144;N=139]
    0
    0
        3rd 15min after patch Category=7[N=144;N=139]
    0
    0
        3rd 15min after patch CombineCategory[N=144;N=139]
    0
    0
        3rd 60min after patch Category=0[N=144;N=138]
    118
    101
        3rd 60min after patch Category=1[N=144;N=138]
    24
    33
        3rd 60min after patch Category=2[N=144;N=138]
    2
    4
        3rd 60min after patch Category=3[N=144;N=138]
    0
    0
        3rd 60min after patch Category=4[N=144;N=138]
    0
    0
        3rd 60min after patch Category=5[N=144;N=138]
    0
    0
        3rd 60min after patch Category=6[N=144;N=138]
    0
    0
        3rd 60min after patch Category=7[N=144;N=138]
    0
    0
        3rd 60min after patch CombineCategory[N=144;N=138]
    0
    0
        4th before EMLA Category=0[N=129;N=130]
    126
    127
        4th before EMLA Category=1[N=129;N=130]
    3
    3
        4th before EMLA Category=2[N=129;N=130]
    0
    0
        4th before EMLA Category=3[N=129;N=130]
    0
    0
        4th before EMLA Category=4[N=129;N=130]
    0
    0
        4th before EMLA Category=5[N=129;N=130]
    0
    0
        4th before EMLA Category=6[N=129;N=130]
    0
    0
        4th before EMLA Category=7[N=129;N=130]
    0
    0
        4th before EMLA CombinedCategory[N=129;N=130]
    0
    0
        4th 15min after patch Category=0[N=129;N=131]
    89
    90
        4th 15min after patch Category=1[N=129;N=131]
    35
    33
        4th 15min after patch Category=2[N=129;N=131]
    5
    8
        4th 15min after patch Category=3[N=129;N=131]
    0
    0
        4th 15min after patch Category=4[N=129;N=131]
    0
    0
        4th 15min after patch Category=5[N=129;N=131]
    0
    0
        4th 15min after patch Category=6[N=129;N=131]
    0
    0
        4th 15min after patch Category=7[N=129;N=131]
    0
    0
        4th 15min after patch CombineCategory[N=129;N=131]
    0
    0
        4th 60min after patch Category=0[N=129;N=131]
    104
    99
        4th 60min after patch Category=1[N=129;N=131]
    22
    25
        4th 60min after patch Category=2[N=129;N=131]
    3
    7
        4th 60min after patch Category=3[N=129;N=131]
    0
    0
        4th 60min after patch Category=4[N=129;N=131]
    0
    0
        4th 60min after patch Category=5[N=129;N=131]
    0
    0
        4th 60min after patch Category=6[N=129;N=131]
    0
    0
        4th 60min after patch Category=7[N=129;N=131]
    0
    0
        4th 60min after patch CombineCategory[N=129;N=131]
    0
    0
        5th before EMLA Category=0[N=122;N=120]
    118
    118
        5th before EMLA Category=1[N=122;N=120]
    4
    2
        5th before EMLA Category=2[N=122;N=120]
    0
    0
        5th before EMLA Category=3[N=122;N=120]
    0
    0
        5th before EMLA Category=4[N=122;N=120]
    0
    0
        5th before EMLA Category=5[N=122;N=120]
    0
    0
        5th before EMLA Category=6[N=122;N=120]
    0
    0
        5th before EMLA CombinedCategory[N=122;N=120]
    0
    0
        5th 15min after patch Category=0[N=122;N=119]
    91
    81
        5th 15min after patch Category=1[N=122;N=119]
    26
    32
        5th 15min after patch Category=2[N=122;N=119]
    5
    6
        5th 15min after patch Category=3[N=122;N=119]
    0
    0
        5th 15min after patch Category=4[N=122;N=119]
    0
    0
        5th 15min after patch Category=5[N=122;N=119]
    0
    0
        5th 15min after patch Category=6[N=122;N=119]
    0
    0
        5th 15min after patch Category=7[N=122;N=119]
    0
    0
        5th 15min after patch CombineCategory[N=122;N=119]
    0
    0
        5th 60min after patch Category=0[N=122;N=120]
    102
    95
        5th 60min after patch Category=1[N=122;N=120]
    17
    18
        5th 60min after patch Category=2[N=122;N=120]
    3
    7
        5th 60min after patch Category=3[N=122;N=120]
    0
    0
        5th 60min after patch Category=4[N=122;N=120]
    0
    0
        5th 60min after patch Category=5[N=122;N=120]
    0
    0
        5th 60min after patch Category=6[N=122;N=120]
    0
    0
        5th 60min after patch Category=7[N=122;N=120]
    0
    0
        5th 60min after patch CombineCategory[N=122;N=120]
    0
    0
        6th before EMLA Category=0[N=108;N=109]
    108
    107
        6th before EMLA Category=1[N=108;N=109]
    0
    2
        6th before EMLA Category=2[N=108;N=109]
    0
    0
        6th before EMLA Category=3[N=108;N=109]
    0
    0
        6th before EMLA Category=4[N=108;N=109]
    0
    0
        6th before EMLA Category=5[N=108;N=109]
    0
    0
        6th before EMLA Category=6[N=108;N=109]
    0
    0
        6th before EMLA Category=7[N=108;N=109]
    0
    0
        6th before EMLA CombinedCategory[N=108;N=109]
    0
    0
        6th 15min after patch Category=0[N=108;N=109]
    84
    78
        6th 15min after patch Category=1[N=108;N=109]
    20
    28
        6th 15min after patch Category=2[N=108;N=109]
    4
    3
        6th 15min after patch Category=3[N=108;N=109]
    0
    0
        6th 15min after patch Category=4[N=108;N=109]
    0
    0
        6th 15min after patch Category=5[N=108;N=109]
    0
    0
        6th 15min after patch Category=6[N=108;N=109]
    0
    0
        6th 15min after patch Category=7[N=108;N=109]
    0
    0
        6th 15min after patch CombineCategory[N=108;N=109]
    0
    0
        6th 60min after patch Category=0[N=108;N=109]
    89
    86
        6th 60min after patch Category=1[N=108;N=109]
    17
    20
        6th 60min after patch Category=2[N=108;N=109]
    2
    3
        6th 60min after patch Category=3[N=108;N=109]
    0
    0
        6th 60min after patch Category=4[N=108;N=109]
    0
    0
        6th 60min after patch Category=5[N=108;N=109]
    0
    0
        6th 60min after patch Category=6[N=108;N=109]
    0
    0
        6th 60min after patch Category=7[N=108;N=109]
    0
    0
        6th 60min after patch CombineCategory[N=108;N=109]
    0
    0
        7th before EMLA Category=0[N=84;N=83]
    84
    83
        7th before EMLA Category=1[N=84;N=83]
    0
    0
        7th before EMLA Category=2[N=84;N=83]
    0
    0
        7th before EMLA Category=3[N=84;N=83]
    0
    0
        7th before EMLA Category=4[N=84;N=83]
    0
    0
        7th before EMLA Category=5[N=84;N=83]
    0
    0
        7th before EMLA Category=6[N=84;N=83]
    0
    0
        7th before EMLA Category=7[N=84;N=83]
    0
    0
        7th before EMLA CombinedCategory[N=84;N=83]
    0
    0
        7th 15min after patch Category=0[N=84;N=82]
    66
    58
        7th 15min after patch Category=1[N=84;N=82]
    15
    22
        7th 15min after patch Category=2[N=84;N=82]
    3
    1
        7th 15min after patch Category=3[N=84;N=82]
    0
    1
        7th 15min after patch Category=4[N=84;N=82]
    0
    0
        7th 15min after patch Category=5[N=84;N=82]
    0
    0
        7th 15min after patch Category=6[N=84;N=82]
    0
    0
        7th 15min after patch Category=7[N=84;N=82]
    0
    0
        7th 15min after patch CombinedCategory[N=84;N=82]
    0
    0
        7th 60min after patch Category=0[N=84;N=83]
    68
    65
        7th 60min after patch Category=1[N=84;N=83]
    14
    15
        7th 60min after patch Category=2[N=84;N=83]
    2
    3
        7th 60min after patch Category=3[N=84;N=83]
    0
    0
        7th 60min after patch Category=4[N=84;N=83]
    0
    0
        7th 60min after patch Category=5[N=84;N=83]
    0
    0
        7th 60min after patch Category=6[N=84;N=83]
    0
    0
        7th 60min after patch Category=7[N=84;N=83]
    0
    0
        7th 60min after patch CombinedCategory[N=84;N=83]
    0
    0
    No statistical analyses for this end point

    Secondary: Tolerability of patch application by "pain now" Numeric Pain Rating Scale (NPRS) scores after patch application (SAF)

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    End point title
    Tolerability of patch application by "pain now" Numeric Pain Rating Scale (NPRS) scores after patch application (SAF) [4]
    End point description
    The “pain now” NPRS uses a 0 to 10 scale to rate discomfort associated with patch application. The “pain now” endpoint of interest was the absolute value of the score within 15 minutes and 60 minutes after patch removal. Results are represented as mean values scores. The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study ( 15 and 60 minutes after patch removal)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Standard of Care (SOC) arm was not reported in the Clinical Study Report.
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects analysed
    156
    157
    Units: Number of Participants
    arithmetic mean (standard deviation)
        15 minutes after patch removal
    2.6 ± 1.93
    2.7 ± 2.03
        60 minutes after patch removal
    2.5 ± 1.99
    2.4 ± 1.93
    No statistical analyses for this end point

    Secondary: Tolerability of patch application by rescue medication (SAF)

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    End point title
    Tolerability of patch application by rescue medication (SAF)
    End point description
    Rescue medication was used for pain associated with patch application and it was used on Days 1 to 5 after patch application only.
    End point type
    Secondary
    End point timeframe
    Days 1 through 5 after each patch application
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    156
    157
    155
    Units: Number of Participants
    number (not applicable)
        Analgesics
    25
    39
    0
        Antiepileptics
    1
    0
    0
        Antihistamines for systemic use
    1
    0
    0
        Antiinflammatory and antirheumatic products
    13
    17
    0
        Antipruritics,inc antihistamines,anesthetics etc
    1
    0
    0
        Antithrombic agents
    1
    1
    0
        Cardiac Therapy
    6
    7
    0
        Cough and Cold Preparations
    0
    1
    0
        Drugs for functional gastrointestinal disorders
    0
    1
    0
        Muscle Relaxants
    0
    1
    0
        Nasal Preparations
    0
    1
    0
        Ophthalmologicals
    4
    5
    0
        Other dermatological preparations
    4
    5
    0
        Other gynecologicals
    6
    7
    0
        Preparations for treatment of wounds and ulcers
    0
    1
    0
        Psychoanaleptics
    1
    0
    0
        Psycholeptics
    1
    1
    0
        Stomatological Preparations
    7
    8
    0
        Topical Products for joint and muscular pain
    14
    17
    0
        Vitamins
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Vital Signs Associated with Patch Applications (heart rate and blood pressure) Absolute Value (SAF)

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    End point title
    Vital Signs Associated with Patch Applications (heart rate and blood pressure) Absolute Value (SAF) [5]
    End point description
    The End of Study (EOS) visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Screening to End of Study (EOS)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Standard of Care (SOC) arm was not reported in the Clinical Study Report.
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects analysed
    156
    157
    Units: Number of Participants
    arithmetic mean (standard deviation)
        Screening
    136.1 ± 14.79
    136.1 ± 15.13
        Before 1st Application
    133.7 ± 14.92
    135.5 ± 12.87
        After 1st Application
    134.7 ± 16.49
    137.7 ± 16.05
        Before 2nd Application
    131.7 ± 12.32
    132.9 ± 12.34
        After 2nd Application
    133.5 ± 12.1
    135.9 ± 13.63
        Before 3rd Application
    132.5 ± 11.59
    131.6 ± 11.4
        After 3rd Application
    134 ± 13.7
    135.1 ± 12.91
        Before 4th Application
    131.6 ± 12.95
    131.9 ± 12.69
        After 4th Application
    133.1 ± 13.73
    135.9 ± 15.09
        Before 5th Application
    131.1 ± 11.22
    134.6 ± 12.03
        After 5th Application
    132.2 ± 12.69
    136.5 ± 12.87
        Before 6th Application
    130.8 ± 10.85
    134.7 ± 12.53
        After 6th Application
    133.8 ± 12.4
    136.2 ± 13.62
        Before 7th Application
    130.4 ± 11.64
    132 ± 12.4
        After 7th Application
    131.9 ± 12.19
    135 ± 12.75
        Before Last Application
    131.7 ± 13.05
    132.4 ± 13.31
        After Last Application
    132.9 ± 14.11
    135.1 ± 14.11
        Before Subject Mean (all Applications)
    132.5 ± 10.3
    133.7 ± 10.13
        After Subject Mean (all Applications)
    133.9 ± 11.55
    136.3 ± 11.68
        EOT- End of Treatment
    132.5 ± 10.96
    133.8 ± 12.29
    No statistical analyses for this end point

    Secondary: Clinical Laboratory Assessments (assessments of HbA1c and lipids profiles) Change from Baseline (SAF)

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    End point title
    Clinical Laboratory Assessments (assessments of HbA1c and lipids profiles) Change from Baseline (SAF)
    End point description
    Laboratory assessments of HbA1c (mmol/mol) and lipids profiles [total cholesterol (mmol/L), low-density lipoprotein [LDL]-cholesterol (mmol/L), high-density lipoprotein [HDL]-cholesterol (mmol/L) and triglycerides (mmol/L)] were collected at screening and bimonthly visits. The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    156
    157
    155
    Units: mmol
    arithmetic mean (standard deviation)
        HbA1c Month 2 [N=141;N=146;N=136]
    1.003 ± 7.4575
    0.908 ± 8.5429
    1.15 ± 10.0739
        HbA1c Month 4 [N=137;N=138;N=137]
    1.711 ± 12.3447
    1.178 ± 10.5664
    1.463 ± 10.4435
        HbA1c Month 6 [N=128;N=131;N=127]
    1.839 ± 10.8738
    1.026 ± 11.1515
    2.143 ± 10.8025
        HbA1c Month 8 [N=122;N=130;N=125]
    1.502 ± 11.6611
    1.406 ± 11.2172
    3.148 ± 11.3131
        HbA1c Month 10 [N=124;N=122;N=124]
    0.58 ± 10.4266
    0.868 ± 11.1243
    2.453 ± 11.7181
        HbA1c Month 12 [N=122;N=122;N=116]
    0.552 ± 10.9702
    0.733 ± 10.685
    3.602 ± 9.9211
        HbA1c EOT (LOCF) [N=144;N=149;N=141]
    0.665 ± 9.8461
    0.625 ± 10.5329
    2.575 ± 10.2414
        Cholesterol Month 2 [N=134;N=139;N=132]
    0.043 ± 1.0555
    0.075 ± 1.1545
    -0.069 ± 0.8523
        Cholesterol Month 4 [N=136;N=140;N=135]
    -0.006 ± 0.9418
    0.072 ± 1.0549
    0.019 ± 1.054
        Cholesterol Month 6 [N=129;N=133;N=129]
    -0.037 ± 1.0284
    -0.036 ± 1.1769
    0.026 ± 0.8913
        Cholesterol Month 8 [N=123;N=130;N=125]
    -0.081 ± 1.0322
    0.113 ± 1.1901
    0.048 ± 1.0848
        Cholesterol Month 10 [N=125;N=122;N=124]
    0.05 ± 1.2105
    0.092 ± 1.2344
    -0.059 ± 1.1542
        Cholesterol Month 12 [N=122;N=122;N=118]
    -0.087 ± 1.0267
    0.274 ± 1.3192
    0.021 ± 1.0095
        Cholesterol EOT(LOCF) [N=143;N=147;N=142]
    -0.104 ± 0.9949
    0.113 ± 1.0187
    0.042 ± 1.0075
        HDL Cholesterol Month 2[N=133;N=138 N=132]
    -0.02 ± 0.2808
    0.025 ± 0.3577
    -0.008 ± 0.3142
        HDL Cholesterol Month 4[N=136;N=139; N=135]
    -0.058 ± 0.4536
    -0.017 ± 0.3606
    -0.002 ± 0.3205
        HDL Cholesterol Month 6[N=129;N=132; N=130]
    -0.037 ± 0.464
    -0.007 ± 0.3921
    -0.008 ± 0.4564
        HDL Cholesterol Month 8[N=123;N=128; N=124]
    -0.013 ± 0.5047
    0.016 ± 0.3474
    0.015 ± 0.3655
        HDL Cholesterol Month 10[N=125;N=120; N=122]
    -0.001 ± 0.4641
    0.005 ± 0.3331
    0.005 ± 0.3242
        HDL Cholesterol Month 12[N=122;N=121; N=118]
    -0.078 ± 0.4306
    0.028 ± 0.2922
    0.028 ± 0.3943
        HDL Cholesterol EOT(LOCF)[N=143;N=146;N=142]
    -0.077 ± 0.3858
    0.094 ± 1.1099
    0.018 ± 0.3873
        LDL Cholesterol Month 2[N=131;N=136;N=130]
    -0.039 ± 0.9793
    -0.079 ± 0.9017
    -0.008 ± 0.8726
        LDL Cholesterol Month 4[N=133;N=137;N=133]
    -0.014 ± 0.8795
    -0.001 ± 0.9254
    -0.082 ± 0.8474
        LDL Cholesterol Month 6[N=127;N=131;N=129]
    -0.131 ± 1.0019
    -0.116 ± 0.9709
    -0.006 ± 0.9436
        LDL Cholesterol Month 8[N=119;N=127;N=123]
    -0.179 ± 1.1248
    -0.04 ± 1.0938
    -0.018 ± 0.9809
        LDL Cholesterol Month 10[N=124;N=118;N=121]
    -0.018 ± 1.1264
    -0.016 ± 0.9429
    -0.006 ± 1.065
        LDL Cholesterol Month 12[N=120;N=120;N=117]
    -0.176 ± 0.9779
    0.05 ± 1.0922
    0.03 ± 0.9678
        LDL Cholesterol EOT(LOCF) [N=141;N=144;N=141]
    -0.117 ± 0.9599
    0.008 ± 0.9434
    0.022 ± 0.937
        Triglycerides Month 2[N=134;N=139;N=133]
    0.068 ± 1.5088
    0.121 ± 1.5031
    -0.057 ± 1.0087
        Triglycerides Month 4[N=134;N=140;N=136]
    -0.071 ± 1.5373
    0.033 ± 1.1793
    0.089 ± 1.0323
        Triglycerides Month 6[N=129;N=133;N=130]
    -0.022 ± 1.6021
    -0.066 ± 1.1939
    0.128 ± 1.0188
        Triglycerides Month 8[N=123;N=130;N=126]
    -0.173 ± 1.4995
    0.021 ± 1.3225
    0.104 ± 1.1094
        Triglycerides Month 10[N=125;N=122;N=124]
    -0.123 ± 1.4794
    0.113 ± 1.8644
    -0.13 ± 1.0656
        Triglycerides Month 12[N=122;N=122;N=118]
    -0.027 ± 1.572
    0.219 ± 2.2574
    -0.033 ± 1.0027
        Triglycerides EOT(LOCF) [N=143;N=147;N=142]
    0.035 ± 1.498
    -0.042 ± 1.4191
    0.072 ± 0.9336
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory -Diabetic Peripheral Neuropathy Question 5 Mean Change from Baseline (Average Pain) (SAF)

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    End point title
    Brief Pain Inventory -Diabetic Peripheral Neuropathy Question 5 Mean Change from Baseline (Average Pain) (SAF)
    End point description
    The BPI is a widely used and validated, patient completed, numeric rating scale (NRS) that measures severity of pain and its interference with daily function. A major benefit of the BPI is its numeric rating scale format, which has been recommended for research on neuropathic pain. The BPI-DN is a modified version of the BPI that has been developed specifically for use in patients with PDPN and includes the 4-item pain Severity scale(Worst Pain, Least Pain, Average Pain, and Pain Now)and the 7-item pain Interference scale (General Activity,Mood, Walking Ability, Normal Work, Relations With Others, Sleep, Enjoyment of Life).The Pain Severity Index is obtained by taking the average of the 4 Pain Severity items and the Pain Interference Index is obtained by taking the average of the 7 Interference Items. Last observation carried forward (LOCF)was imputed and Safety Analysis Set (SAF) was used for analysis. The EOS visit for 30 &60 min was between 8 & 12 weeks after patch and SOC 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    153
    155
    148
    Units: Number of participants
        arithmetic mean (standard deviation)
    -2 ± 1.82
    -2.3 ± 2.11
    -1.1 ± 2.01
    Statistical analysis title
    BPI-Mean change Q5 Qutenza 30 min versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in average pain based on the Brief Pain Inventory question 5.
    Comparison groups
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC v SOC (Standard of Care)
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    -0.6
    Statistical analysis title
    BPI-Mean change Q5 Qutenza 60 min versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in average pain based on the Brief Pain Inventory question 5.
    Comparison groups
    SOC (Standard of Care) v Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.9

    Secondary: Brief Pain Inventory-Diabetic Neuropathy (Pain Severity Index) (SAF)

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    End point title
    Brief Pain Inventory-Diabetic Neuropathy (Pain Severity Index) (SAF)
    End point description
    Data presented represents mean change from Baseline to EOS in Pain Severity Index (Safety Analysis Set). The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    153
    155
    148
    Units: Number of participants
        arithmetic mean (standard deviation)
    -1.9 ± 1.8
    -2.2 ± 1.89
    -0.9 ± 1.71
    Statistical analysis title
    BPI-Pain Severity Qutenza 30 min versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in Pain Severity Index.
    Comparison groups
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC v SOC (Standard of Care)
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    -0.6
    Statistical analysis title
    BPI-Pain Severity Qutenza 60 min versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in Pain Severity Index.
    Comparison groups
    SOC (Standard of Care) v Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.9

    Secondary: Patient Global Impression of Change (SAF)

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    End point title
    Patient Global Impression of Change (SAF)
    End point description
    The PGIC is a patient-rated instrument that measures change in patients’ overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Counts by combined categories [Very Much + Much Improved][Very Much + Much + Minimally Improved] and [No change + Minimally Worse + Much Worse] are reported for this endpoint. The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS).
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    153
    155
    148
    Units: number of participants
    number (not applicable)
        Very much improved + much improved
    37
    38
    14
        Very much impr + much impr +min improved
    103
    110
    57
        No change + min worse+much worse+very much worse
    50
    45
    91
    No statistical analyses for this end point

    Secondary: EQ-5D (European Quality of Life Questionnaire in 5 Dimensions) Questionnaire Change from Baseline (SAF)

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    End point title
    EQ-5D (European Quality of Life Questionnaire in 5 Dimensions) Questionnaire Change from Baseline (SAF)
    End point description
    The EQ-5D is used to assess patients health-related quality of life (HRQoL). The EQ-5D self-reported questionnaire includes a visual analog scale (VAS), which records the patient's self-rated health status on a graduated (0 to 100) scale, with higher scores for higher HRQoL. It also includes the EQ-5D descriptive system, which comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    156
    157
    155
    Units: Number of participants
    arithmetic mean (standard deviation)
        Month 2 [N=145;N=149;N=141]
    2.7 ± 15.5
    2 ± 17.57
    3 ± 17.58
        Month 4 [N=137;N=135;N=136]
    5.5 ± 16.75
    5.8 ± 17.32
    2.9 ± 18.6
        Month 6 [N=130;N=133;N=130]
    7.2 ± 16.92
    8.4 ± 18.39
    3.7 ± 17.62
        Month 8 [N=125;N=130;N=125]
    11.1 ± 18.95
    10.2 ± 19.12
    3.6 ± 17.95
        Month 10 [N=125;N=121;N=127]
    8.3 ± 19.24
    12.3 ± 18.51
    4.9 ± 16.78
        Month 12 [N=121;N=120;N=122]
    10.5 ± 17.34
    12.2 ± 20.11
    6.2 ± 19.23
        Month 13 [N=26;N=27;N=81]
    9.3 ± 21.89
    9.2 ± 17.02
    5.6 ± 16.76
        Month 14 [N=87;N=83;N=5]
    12.8 ± 17.05
    14.3 ± 21.02
    -5.4 ± 12.78
        Month 15 [N=14;N=13;N=0]
    10.6 ± 20.09
    2.8 ± 22.73
    0 ± 0
        EOT (LOCF)[N=149;N=151;N=145]
    10.4 ± 18.52
    11.2 ± 21.42
    5.5 ± 18.07
    No statistical analyses for this end point

    Secondary: Treatment satisfaction using the Self-Assessment of Treatment (SAT) questionnaire (SAF)

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    End point title
    Treatment satisfaction using the Self-Assessment of Treatment (SAT) questionnaire (SAF)
    End point description
    The Self-Assessment of Treatment (SAT) assessed treatment satisfaction by using a 5-point Likert-type scale ranging from -2 (a strong negative response) to 2 (a strong positive response) and zero indicating a neutral response. The questionnaire contains each of the following questions, How do you assess your pain level after treatment in this study?How do you assess your activity level after treatment in this study? How has your quality of life changed after treatment in this study?; Would you undergo this treatment again?; How do you compare the treatment you received in this study to previous medication or therapies for your pain?. The SAT variables of interest were counts by category, counts by combined categories (Worse: (-2) + (-1), Not Better or Worse: (-2) + (-1) + (0), Better: (1) + (2). The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    156
    157
    155
    Units: Number of participants
    number (not applicable)
        Pain level better[N=145;N=144;N=139]
    94
    103
    45
        Pain level worse[N=145;N=144;N=139]
    13
    10
    26
        Activity level better[N=145;N=144;N=139]
    73
    78
    31
        Activity level worse[N=145;N=144;N=139]
    18
    12
    16
        Quality of life better[N=145;N=144;N=139]
    78
    93
    44
        Quality of life worse[N=145;N=144;N=139]
    12
    8
    21
    No statistical analyses for this end point

    Secondary: Use of Concomitant Medications (SAF)

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    End point title
    Use of Concomitant Medications (SAF)
    End point description
    Use of medications of interest at baseline and at the end of the treatment. The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline and End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    156
    157
    155
    Units: Number of participants
    number (not applicable)
        Baseline Antidepressants[N=156 N=157 N=155]
    17
    8
    12
        Baseline Antiepileptic drugs [N=156 N=157 N=155]
    44
    49
    50
        Baseline Opioids[N=156 N=157 N=155]
    17
    9
    13
        EOT Antidepressants[N=146 N=147 N=146]
    16
    10
    22
        EOT Antiepileptic drugs[N=146 N=147 N=146]
    43
    53
    63
        EOT Opioids[N=146 N=147 N=146]
    16
    12
    17
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory Diabetic Neuropathy (Pain Interference)(SAF)

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    End point title
    Brief Pain Inventory Diabetic Neuropathy (Pain Interference)(SAF)
    End point description
    Data represents mean change from Baseline to End of Treatment in Pain Interference (Safety Analysis Set). The EOS visit for Qutenza 30 min (arm I) & 60 min (arm II) took place between 8 and 12 weeks after last patch application and for SOC (arm III) between week 52-56.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    153
    154
    148
    Units: Number of participants
        arithmetic mean (standard deviation)
    -1.9 ± 2.09
    -2 ± 2.28
    -0.8 ± 1.85
    Statistical analysis title
    BPI-Pain Interference Qutenza (30 min) versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in Pain Interference.
    Comparison groups
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC v SOC (Standard of Care)
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    -0.6
    Statistical analysis title
    BPI-Pain Interference Qutenza (60 min) versus SOC
    Statistical analysis description
    Mean change from baseline to End of Study (EOS) in Pain Interference.
    Comparison groups
    SOC (Standard of Care) v Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.8

    Secondary: Average Sensory Testing Score per Modality (SAF)

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    End point title
    Average Sensory Testing Score per Modality (SAF)
    End point description
    Sensory testing involved ratings of evoked sensations and pain by recording reduced or increased stimulus perception. It involved the assessment of 5 modalities: vibration, heat, cold and sharp sensations and the assessment of deep tendon reflexes. The left and right sides were assessed separately as; [Vibration sensation: not felt (= 0), < 6 sec (= 1), 6 to 10 sec (= 2), > 10 sec (= 3, normal)] [Reflexes: no response (= 0), hypoactive (= 1), normal (= 2),hyperactive (= 3), clonus (= 4)],[Heat at each of ball of foot, mid-plantar, dorsal first toe, dorsal foot, medial malleolus: not warm (= 0), slightly warm (= 1), warm or hot (= 2, normal), painfully hot (= 3)], [Cold at each of ball of foot, mid-plantar, dorsal first toe, dorsal foot, medial malleolus: not cold (= 0), slightly cold (= 1), cold (= 2, normal), painfully cold (= 3)] [Sharp at each ball of foot, mid-plantar, dorsal first toe, dorsal foot, medial malleolus not felt(=0),dull(=1),sharp (= 2, normal), painfully sharp (= 3)]
    End point type
    Secondary
    End point timeframe
    Baseline to End of Study (EOS)[EOS defined for arms Qutenza 30 min & 60 min between 8 and 12 weeks after last patch application and SOC between week 52-56]
    End point values
    Qutenza (Capsaicin (8%) high-concentration patch) 30 min & SOC Qutenza (Capsaicin (8%) high-concentration patch) 60 min & SOC SOC (Standard of Care)
    Number of subjects analysed
    156
    157
    155
    Units: Number
    arithmetic mean (standard deviation)
        Baseline Vibration [N=153;148;150]
    0.9 ± 0.79
    0.9 ± 0.75
    1 ± 0.71
        Month 2 Vibration [N=150;153;145]
    0.9 ± 0.79
    0.9 ± 0.76
    1 ± 0.75
        Month 4 Vibration [N=141;142;140]
    1 ± 0.86
    1.1 ± 0.83
    1 ± 0.78
        Month 6 Vibration [N=132;135;133]
    1 ± 0.78
    1.1 ± 0.8
    1 ± 0.75
        Month 8 Vibration [N=128;133;127]
    1.1 ± 0.78
    1.2 ± 0.85
    1.1 ± 0.68
        Month 10 Vibration [N=128;125;129]
    1.1 ± 0.8
    1.1 ± 0.8
    1.1 ± 0.74
        Month 12 Vibration [N=126;124;126]
    1.2 ± 0.79
    1.2 ± 0.8
    1.1 ± 0.74
        Month 13 Vibration [N=26;29;82]
    1 ± 0.87
    1.2 ± 0.82
    1.1 ± 0.75
        Month 14 Vibration [N=90;84;5]
    1.1 ± 0.75
    1.1 ± 0.86
    1 ± 0.71
        Month 15 Vibration [N=14;13;0]
    1.4 ± 0.77
    1.3 ± 0.83
    0 ± 0
        EOT(LOCF) Vibration[N=153;155;147]
    1 ± 0.79
    1.1 ± 0.81
    1.1 ± 0.78
        Baseline Reflexes [N=153;148;150]
    0.5 ± 0.66
    0.6 ± 0.72
    0.6 ± 0.64
        Month 2 Reflexes [N=150;153;145]
    0.5 ± 0.65
    0.5 ± 0.69
    0.6 ± 0.7
        Month 4 Reflexes [N=141;142;140]
    0.5 ± 0.62
    0.5 ± 0.68
    0.5 ± 0.62
        Month 6 Reflexes [N=132;135;133]
    0.5 ± 0.63
    0.6 ± 0.71
    0.5 ± 0.63
        Month 8 Reflexes [N=128;133;127]
    0.5 ± 0.63
    0.6 ± 0.68
    0.5 ± 0.64
        Month 10 Reflexes [N=128;125;129]
    0.6 ± 0.69
    0.6 ± 0.73
    0.6 ± 0.65
        Month 12 Reflexes [N=126;124;126]
    0.6 ± 0.74
    0.6 ± 0.7
    0.6 ± 0.69
        Month 13 Reflexes [N=26;29;82]
    0.7 ± 0.75
    0.7 ± 0.68
    0.8 ± 0.69
        Month 14 Reflexes [N=90;84;5]
    0.5 ± 0.64
    0.5 ± 0.67
    0.4 ± 0.55
        Month 15 Reflexes [N=14;13;0]
    0.9 ± 0.95
    0.7 ± 0.67
    0 ± 0
        EOT(LOCF) Reflexes[N=153;155;147]
    0.6 ± 0.72
    0.6 ± 0.7
    0.6 ± 0.69
        Baseline Heat[N=153;148;150]
    0.8 ± 0.56
    0.8 ± 0.51
    0.8 ± 0.52
        Month 2 Heat[N=150;153;145]
    0.8 ± 0.52
    0.9 ± 0.54
    0.8 ± 0.55
        Month 4 Heat[N=141;142;140]
    0.9 ± 0.53
    1 ± 0.54
    0.8 ± 0.5
        Month 6 Heat[N=132;135;133]
    0.9 ± 0.54
    1 ± 0.55
    0.9 ± 0.52
        Month 8 Heat[N=128;133;127]
    0.9 ± 0.55
    1.1 ± 0.54
    0.9 ± 0.56
        Month 10 Heat[N=128;125;129]
    1 ± 0.56
    1.1 ± 0.58
    0.9 ± 0.56
        Month 12 Heat[N=126;124;126]
    1 ± 0.6
    1.2 ± 0.57
    1 ± 0.58
        Month 13 Heat[N=26;29;82]
    1.2 ± 0.72
    1.2 ± 0.59
    1 ± 0.57
        Month 14 Heat[N=90;84;5]
    1 ± 0.57
    1.2 ± 0.62
    1.2 ± 0.69
        Month 15 Heat[N=14;13;0]
    1.2 ± 0.58
    1 ± 0.52
    0 ± 0
        EOT (LOCF) Heat[N=153;155;147]
    1 ± 0.62
    1.1 ± 0.59
    0.9 ± 0.59
        Baseline Cold[N=153;148;150]
    1 ± 0.58
    1.1 ± 0.59
    1.1 ± 0.61
        Month 2 Cold [N=150;153;145]
    1.1 ± 0.57
    1.2 ± 0.55
    1.1 ± 0.59
        Month 4 Cold [N=141;142;140]
    1.1 ± 0.56
    1.2 ± 0.61
    1.1 ± 0.57
        Month 6 Cold [N=132;135;133]
    1.2 ± 0.56
    1.2 ± 0.56
    1.2 ± 0.57
        Month 8 Cold [N=128;133;127]
    1.2 ± 0.57
    1.2 ± 0.58
    1.2 ± 0.56
        Month 10 Cold [N=128;125;129]
    1.2 ± 0.58
    1.4 ± 0.59
    1.2 ± 0.57
        Month 12 Cold [N=126;124;126]
    1.2 ± 0.62
    1.3 ± 0.58
    1.2 ± 0.57
        Month 13 Cold [N=26;29;82]
    1.2 ± 0.72
    1.4 ± 0.6
    1.2 ± 0.58
        Month 14 Cold [N=90;84;5]
    1.2 ± 0.59
    1.4 ± 0.62
    1.2 ± 0.69
        Month 15 Cold [N=14;13;0]
    1.6 ± 0.66
    1.4 ± 0.46
    0 ± 0
        EOT(LOCF) [N=153;155;147]
    1.2 ± 0.63
    1.3 ± 0.58
    1.1 ± 0.61
        Baseline Sharp [N=153;148;150]
    1 ± 0.59
    1 ± 0.58
    1.1 ± 0.55
        Month 2 Sharp [N=150;153;145]
    1 ± 0.54
    1.1 ± 0.54
    1.1 ± 0.53
        Month 4 Sharp [N=141;142;139]
    1.1 ± 0.57
    1.2 ± 0.56
    1.1 ± 0.54
        Month 6 Sharp [N=132;135;133]
    1.1 ± 0.53
    1.2 ± 0.54
    1.2 ± 0.51
        Month 8 Sharp [N=128;133;127]
    1.1 ± 0.56
    1.2 ± 0.54
    1.2 ± 0.51
        Month 10 Sharp [N=128;125;129]
    1.2 ± 0.51
    1.3 ± 0.53
    1.2 ± 0.51
        Month 12 Sharp [N=126;124;126]
    1.2 ± 0.58
    1.3 ± 0.56
    1.1 ± 0.55
        Month 13 Sharp [N=26;29;82]
    1.2 ± 0.73
    1.3 ± 0.5
    1.3 ± 0.55
        Month 14 Sharp [N=90;84;5]
    1.2 ± 0.58
    1.3 ± 0.61
    1.2 ± 0.32
        Month 15 Sharp [N=14;13;0]
    1.4 ± 0.61
    1.3 ± 0.56
    0 ± 0
        EOT(LOCF) Sharp [N=153;155;147]
    1.2 ± 0.61
    1.2 ± 0.6
    1.2 ± 0.54
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to End of Treatment (EOT).
    Adverse event reporting additional description
    A treatment-emergent adverse event (TEAE) was an AE observed after starting administration of the test drug thus, there were no TEAEs in the SOC alone arm.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Qutenza (30 min) + SOC
    Reporting group description
    -

    Reporting group title
    Qutenza (60 min) + SOC
    Reporting group description
    -

    Serious adverse events
    Qutenza (30 min) + SOC Qutenza (60 min) + SOC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 156 (12.82%)
    13 / 157 (8.28%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery diseases
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial hypotension
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 156 (1.28%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system infection
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 156 (1.92%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Qutenza (30 min) + SOC Qutenza (60 min) + SOC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 156 (49.36%)
    84 / 157 (53.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 156 (1.92%)
    10 / 157 (6.37%)
         occurrences all number
    3
    11
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    8 / 156 (5.13%)
    3 / 157 (1.91%)
         occurrences all number
    9
    3
    Glycosylated haemoglobin increased
         subjects affected / exposed
    9 / 156 (5.77%)
    5 / 157 (3.18%)
         occurrences all number
    9
    8
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    15 / 156 (9.62%)
    15 / 157 (9.55%)
         occurrences all number
    22
    39
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    12 / 156 (7.69%)
    14 / 157 (8.92%)
         occurrences all number
    32
    36
    Application site pain
         subjects affected / exposed
    44 / 156 (28.21%)
    46 / 157 (29.30%)
         occurrences all number
    129
    122
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 156 (5.13%)
    5 / 157 (3.18%)
         occurrences all number
    10
    5
    Pain in extremity
         subjects affected / exposed
    8 / 156 (5.13%)
    14 / 157 (8.92%)
         occurrences all number
    18
    31
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 156 (0.00%)
    8 / 157 (5.10%)
         occurrences all number
    0
    9
    Nasopharyngitis
         subjects affected / exposed
    4 / 156 (2.56%)
    9 / 157 (5.73%)
         occurrences all number
    6
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2011
    The original study protocol dated 11 April 2011 was amended (prior to study enrolment) via substantial amendment 1 on 11 July 2011. Amendment 1 included removal of an exclusion criterion for diabetic retinopathy (exclusion criterion 6), an amendment to exclusion criterion 2 to provide a more precise definition of onychomycosis and to clarify that questionnaires were to be completed on paper.
    17 Apr 2013
    Amendment 3 dated 17 April 2013 described comprehensive foot examinations which should have been conducted at every scheduled visit, to identify high risk foot conditions. In this amendment previously mandatory comprehensive diabetes foot exam was made optional.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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