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    Clinical Trial Results:
    Qutenza TM versus pregabalin in patients with Peripheral Neuropathic Pain (PNP) an Open-label, Randomized, Multicenter, Non-inferiority Efficacy and Tolerability Study.

    Summary
    EudraCT number
    		 2011-005872-41
    Trial protocol
    		 SE   CZ   FI   AT   SK   ES   BE   SI   GB   DE   GR   PT   IT   BG  
    Global end of trial date
    26 Sep 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Jun 2016
    First version publication date
    22 May 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updates required due to non-substantial reasons

    Trial information

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    Trial identification
    Sponsor protocol code
    QTZ-EC-0004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01713426
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe Ltd.
    Sponsor organisation address
    2000 Hillswood Drive, Chertsey, United Kingdom, KT16 0RS
    Public contact
    Associate Medical Director - Pain Therapeutic Area, Astellas Pharma Europe Ltd. (APEL), Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Associate Medical Director - Pain Therapeutic Area, Astellas Pharma Europe Ltd. (APEL), 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
    26 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective of the trial was to compare the efficacy,tolerability and impact on health-related quality of life (HRQoL) of treatment with Qutenza (Capsaicin (8%) high-concentration patch) versus pregabalin in patients with Peripheral Neuropathic Pain (PNP) after 8 weeks.
    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 or and regional and national legislation related to the privacy and protection of personal information.The appropriate Competent Authority in each country approved the protocol prior to the start of the study. The original study protocol and the amendments were reviewed by the Independent Ethics Committee (IEC) at each study site. An IEC-approved written informed consent was obtained from each patient or legal guardian prior to the initiation of any study-specific procedures.
    Background therapy
    		 Patients remained on existing neuropathic pain medication(s) if the doses were maintained stable for more than 4 weeks prior to the baseline visit. Patients in the Qutenza (Capsaicin (8%) high-concentration patch) arm received a topical anesthetic on their painful affected area(s) prior to placement of Qutenza (Capsaicin (8%) high-concentration patch). In addition patients may have received a short-acting pain medication (including short-acting opioids) during patch application or as needed following patch application, to reduce patch-related pain/discomfort. Short-acting opioids could have been administered for up to 5 days following patch application. Patients could also be give non-opioid pain medications (e.g., paracetamol, NSAIDs) administered for conditions other than neuropathic pain. Other medical therapy not specifically prohibited, includes non-opioid pain medications (e.g., paracetamol, NSAIDs) administered for conditions other than neuropathic pain. Any changes, additions or discontinuations to medications were assessed and recorded at every study visit. Doses of any concomitant medication for the treatment of neuropathic pain had to remain stable for the duration of the study.
    Evidence for comparator
    		 Pregabalin belongs to the antiepileptic group of drugs and the active substance is a gamma-aminobutyric acid analogue. Pregabalin binds to an auxiliary subunit of voltage-gated calcium channels in the central nervous system, potently displacing 3H-gabapentin. Pregabalin is an anticonvulsant, which, along with tricyclic antidepressants such as amitriptyline can be considered the standard of care for the treatment of PNP. A flexible dose design has been chosen for pregabalin to best match clinical practice in Europe. The Summary of Product Characteristics (SmPC) for pregabalin states that the effective dose range is 150 to 600 mg/day. The SmPC advises that the dose of pregabalin should be up-titrated over a period of 10 to 14 days. To reduce the occurrence of dose-limiting side effects, up-titration of the dose in European clinical practice is often performed over a longer time period, using varying dose changes and frequency of up-titration steps. This study was designed to reflect as much as possible the current clinical practice and thus included an up-titration scheme performed over a period of 4 weeks, using gradual steps of 75 mg/day. This up-titration method was intended to provide a level of flexibility while minimizing variability and represents a compromise between the different clinical practices across Europe. Intolerance of any dose of pregabalin was recorded as an Adverse Event (AE).
    Actual start date of recruitment
    11 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 66
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Slovakia: 14
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Bulgaria: 54
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Greece: 21
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 37
    Country: Number of subjects enrolled
    Belarus: 8
    Country: Number of subjects enrolled
    Romania: 62
    Country: Number of subjects enrolled
    Russian Federation: 56
    Country: Number of subjects enrolled
    Turkey: 49
    Country: Number of subjects enrolled
    Armenia: 40
    Worldwide total number of subjects
    568
    EEA total number of subjects
    415
    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)
    413
    From 65 to 84 years
    155
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multinational, multicenter study was conducted at 92 contracted sites in a total of 22 countries. The study population consisted of males and females between 18 and 80 years of age with documented diagnosis of probable or definite PNP.

    Pre-assignment
    Screening details
    		 Patients were screened in a 12-day period between Day -12 and Day -4 during which informed consent,collection of demographic, medical and medication history, a physical examination, vital signs (blood pressure and pulse rate) and safety laboratory tests data was collected.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Qutenza [Capsaicin (8%) high-concentration patch]
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Qutenza (Capsaicin (8%) high-concentration patch)
    Investigational medicinal product code
    ASP0805
    Other name
    Pharmaceutical forms
    Cutaneous patch
    Routes of administration
    Topical use
    Dosage and administration details
    Qutenza is a high concentration (8%) capsaicin patch. Participants received a topical anesthetic cream (e.g., 4% lidocaine cream) on their painful affected area(s) prior to placement of Qutenza patches. Up to 4 patches of Qutenza (1120 cm2) were applied for 60 minutes to the painful areas of the body (as defined by the study physician), except the feet, where a 30 minute application time was used. The patches were removed after 30 minutes (feet) or 60 minutes (other body locations) and the treatment area(s) were cleansed using study-supplied cleansing gel. The rationale for the application times was to keep the mode of administration in full accordance with the approved SmPC.

    Arm title
    		 Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pregabalin [75 mg hard capsule to be taken orally gamma-aminobutyric acid analogue]
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pregablin was administered daily in 75-mg capsules to best match clinical practice in Europe. Patients were prescribed 150 to 600 mg/day of pregabalin, administered in 2 or 3 divided doses daily. All patients started with a daily dose of 75-mg which was up-titrated to 150 mg/day after 3 or 4 days. Further up-titration was at the discretion of the investigator, however patients were up-titrated to a maximum tolerated dose or until the patient experienced a clinically meaningful reduction in pain (≥ 30% reduction in pain from Baseline). Up-titration occurred in 75-mg steps every 3 to 4 days, up to a maximum dose of 600 mg/day. If the patient experienced unacceptable tolerability issues, a single down-titration of pregabalin was permissible, back to the previously tolerated dose (to a minimum dose of 150 mg/day).

    Number of subjects in period 1
    		Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Started
    286
    282
    Completed
    276
    236
    Not completed
    10
    46
         Consent withdrawn by subject
    4
    14
         Randomized - Never received study drug
    4
    5
         Discontinuation due to AE
    -
    24
         Lack of efficacy
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Qutenza [Capsaicin (8%) high-concentration patch]
    Reporting group description
    		 -

    Reporting group title
    Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Reporting group description
    		 -

    Reporting group values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated] Total
    Number of subjects
    		 286 282 568
    Age categorical
    Units: Subjects
    Age continuous
    Age values reported are for the Full Analysis Set (FAS) population. The FAS population includes all randomized patients who initiated the study treatment. The total number of patients for FAS population was 559, with 282 for Qutenza and 277 for pregabalin.
    Units: years
        arithmetic mean (standard deviation)
    		 55.4 ( 13.96 ) 56.3 ( 13.54 ) -
    Gender categorical
    Gender values provided are for the Full Analysis Set (FAS) population. The FAS population includes all randomized patients who initiated the study treatment. The total number of patients for FAS population was 559, with 282 for Qutenza and 277 for pregabalin.
    Units: Subjects
        Female
    		 159 155 314
        Male
    		 123 122 245
        Not Recorded
    		 4 5 9
    Race
    Race values provided are for the Full Analysis Set (FAS) population. The FAS population included all randomized patients who initiated study treatment. The number of patients for FAS was as follows; Qutenza 282; pregabalin 277.
    Units: Subjects
        White
    		 278 276 554
        Asian
    		 1 1 2
        Other
    		 3 0 3
        Not Recorded
    		 4 5 9
    Type of neuropathic pain
    Postherpetic neuralgia (PHN) is a peripheral neuropathic pain (PNP) disorder that represents a complication of acute herpes zoster infection. Peripheral nerve injury (PNI) can lead to the development of neuropathic pain which results from a trauma or is a consequence of medical interventions such as surgery, injections or radiotherapy. In a majority of patients pain resulting from an injury to peripheral nerves resolves but in some it may become chronic. Non-diabetic painful Peripheral Polyneuropathy is a pattern of nerve damage.
    Units: Subjects
        Postherpetic Neuralgia (PHN)
    		 63 73 136
        Peripheral Nerve Injury (PNI)
    		 146 137 283
        Non-diabetic painful peripheral polyneuropathy
    		 73 67 140
        Not Recorded
    		 4 5 9
    Duration of neuropathic pain diagnosis
    Duration of neuropathic pain diagnosis values are provided for the Full Analysis Set (FAS) population. The FAS population includes all randomized patients who initiated study treatment. The total number of patients randomized for FAS population was 559 with 282 for Qutenza and 277 for pregabalin.
    Units: Years
        arithmetic mean (standard deviation)
    		 2.58 ( 4.32 ) 2.12 ( 2.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Qutenza [Capsaicin (8%) high-concentration patch]
    Reporting group description
    		 -

    Reporting group title
    Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Reporting group description
    		 -

    Primary: Proportion of patients who achieved ≥30% change in the “Average Pain for the Past 24 hours” Numeric Pain Rating Scale (NPRS) Score from Baseline to Week 8 (BOCF) (FAS)

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    End point title
    		 Proportion of patients who achieved ≥30% change in the “Average Pain for the Past 24 hours” Numeric Pain Rating Scale (NPRS) Score from Baseline to Week 8 (BOCF) (FAS)
    End point description
    The proportion of patients in each arm who achieved at least ≥30% change in the “average pain for the past 24 hours” Numeric Pain Rating Scale (NPRS) score from Week 2 (Day 8) to Week 8 (Day 57) was analyzed to compare the efficacy of Qutenza versus pregabalin in patients with Peripheral Neuropathic Pain (PNP). 'Baseline' refers to the mean of all NPRS “average pain for the past 24 hours” scores recorded during the screening period for 4 consecutive days. Week 8 Baseline-Observation Carried Forward (BOCF) refers to the mean of all “average pain for the past 24 hours” NPRS scores for the 7 days up to and including the Week 8 visit if non-missing and the Baseline value if missing assessment at Week 8.
    End point type
    Primary
    End point timeframe
    Week 2 (Day 8) and Week 8 (Day 57)
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number of patients
    number (not applicable)
        Responders, Number of patients
    157
    151
    Statistical analysis title
    		 Proportion of patients who achieved ≥ 30% change
    Statistical analysis description
    The analysis of the primary efficacy variable was performed using a Generalized Linear Model (GLM) with logit link function, the hypothesis was tested using Odds Ratio (OR) using the non-inferiority margin of -8.5%, which translated into a margin on the OR of 0.693. The null hypothesis of inferiority was therefore to be rejected if the 2-sided 95% Confidence Interval (CI) for the OR of Qutenza versus pregabalin fell completely above 0.693.
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.86
    Method
    		 Generalized Linear Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.034
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.715
         upper limit
    		 1.496

    Secondary: Proportion of patients in each arm who achieved “optimal therapeutic effect” from Week 2 to Week 8 (FAS)

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    End point title
    		 Proportion of patients in each arm who achieved “optimal therapeutic effect” from Week 2 to Week 8 (FAS)
    End point description
    The key secondary efficacy endpoint was the proportion of patients who achieved optimal therapeutic effect defined as no change in chronic background pain medication (assessed by the Independent Data Review Board [IDRB]) and no discontinuation of study drug due to lack of efficacy or tolerability prior to Week 8 and at least 30% reduction in the “average pain for the past 24 hours” NPRS score, from Baseline to Week 8 and no moderate or severe Adverse Drug Reaction (ADRs) during the stable treatment period.
    End point type
    Secondary
    End point timeframe
    Week 2 (Day 8) to Week 8 (Day 57)
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number of patients
    number (not applicable)
        Responders, Number of patients
    147
    124
    Statistical analysis title
    		 Optimal therapeutic effect Week 8 BOCF
    Statistical analysis description
    The Generalized Linear Model (GLM) models optimal therapeutic effect dependent on treatment, countries [countries were pooled due to a small numbers of patients within the country] gender with logit linkage and binomial distribution. Baseline Observation Carried Forward (BOCF) and Full Analysis Set (FAS) was used for data analysis.
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.064
    Method
    		 t-test, 2-sided
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.423
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.979
         upper limit
    		 2.066
    Notes
    [1] - Generalized Linear Model

    Secondary: Proportion of patients who achieved at least a 30% change in the “average pain for the past 24 hours" Numeric Pain Rating Scale (NPRS) score from Baseline to the mean of all scores recorded between Week 2 and Week 8 (FAS)

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    End point title
    		 Proportion of patients who achieved at least a 30% change in the “average pain for the past 24 hours" Numeric Pain Rating Scale (NPRS) score from Baseline to the mean of all scores recorded between Week 2 and Week 8 (FAS)
    End point description
    Proportion of patients who achieved at least a 30% decrease in the “average pain for the past 24 hours" Numeric Pain Rating Scale (NPRS) score from Baseline to the mean of all scores recorded between Week 2 and Week 8. BOCF: Baseline Observation Carried Forward and NC [Non-compliant].
    End point type
    Secondary
    End point timeframe
    Baseline to the mean of all scores recorded between Week 2 and Week 8 including complete 8 weeks of treatment.
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number
    number (not applicable)
        Week 8 BOCF+NC
    150
    146
        Week 8 [Mean of all observed data]
    157
    151
    Statistical analysis title
    		 At least 30% Pain Change Achievement Week 8
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.303
    Method
    		 Generalized Linear Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.812
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.547
         upper limit
    		 1.206
    Notes
    [2] - The GLM models optimal therapeutic effect dependent on treatment, country (pooled), gender with logit linkage and Binomial Distribution.The Odds Ratio (OR) compares Qutenza to pregabalin.
    Statistical analysis title
    		 At least 30% Pain Change Achievement Week 8BOCF+NC
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.98
    Method
    		 Generalized Linear Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.695
         upper limit
    		 1.452
    Notes
    [3] - The GLM models optimal therapeutic effect dependent on treatment, country (pooled), gender with logit linkage and Binomial Distribution.The Odds Ratio compares Qutenza to pregabalin.

    Secondary: Proportion of patients who achieved at least a 50% change in the “average pain for the 24 hours" Numeric Pain Rating Scale (NPRS) score from Baseline to Week 8 and from Baseline to the mean of all scores recorded between Week 2 and Week 8 (FAS)

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    End point title
    		 Proportion of patients who achieved at least a 50% change in the “average pain for the 24 hours" Numeric Pain Rating Scale (NPRS) score from Baseline to Week 8 and from Baseline to the mean of all scores recorded between Week 2 and Week 8 (FAS)
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 8, and from Baseline to the mean of all scores recorded between Week 2 and Week 8 including proportion of patients in both arms who completed 8 weeks of treatment.
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number of Patients
    number (not applicable)
        Week 8 [Responders, Number of Patients]
    114
    106
        Week 8 (BOCF) [Responders, Number of Patients]
    114
    106
        Week 2 to Week 8 [Responders, Number of Patients]
    96
    60
    Statistical analysis title
    		 At least 50% Pain Change Achievement Week 8
    Statistical analysis description
    Full Analysis Set (FAS) used for analysis.
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Difference in Proportion
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.6
         upper limit
    		 5.8
    Notes
    [4] - The difference in proportion method was used to analyse large sample normal approximation and compare Qutenza to Pregabalin.
    Statistical analysis title
    		 At least 50% Pain Reduction Achievement Week 8BOCF
    Statistical analysis description
    Full Analysis Set (FAS) was used for analysis.
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Difference in Proportion
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 10.3
    Notes
    [5] - The difference in proportion method was used to analyse large sample normal approximation and compare Qutenza to Pregabalin.
    Statistical analysis title
    		 At Least 50% Reduction Achievement Week 2 to 8
    Statistical analysis description
    Full Analysis Set (FAS) was used for analysis.
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Difference in Proportion
    Point estimate
    12.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.8
         upper limit
    		 19.6
    Notes
    [6] - The difference in proportion method was used to analyse large sample normal approximation and compare Qutenza to Pregabalin.

    Secondary: Absolute and percent change in “average pain for the past 24 hours” Numeric Pain Rating Scale (NPRS) score from Week 2 to Week 8 (FAS)

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    End point title
    		 Absolute and percent change in “average pain for the past 24 hours” Numeric Pain Rating Scale (NPRS) score from Week 2 to Week 8 (FAS)
    End point description
    Full Analysis Set (FAS) was used for data analysis.
    End point type
    Secondary
    End point timeframe
    Mean of all scores from Week 2 (Day 8) to Week 8 (Day 57).
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    275
    Units: Number of Patients
    arithmetic mean (standard deviation)
        Week 2 to 8 Absolute Change from Baseline
    -2.5 ( 2.17 )
    -1.8 ( 1.67 )
        Week 2 to 8 Percent Change from Baseline
    -37.1 ( 30.43 )
    -27.5 ( 24.03 )
    Statistical analysis title
    		 Numeric Pain Rating Scale (NPRS) Absolute Change
    Statistical analysis description
    The LS mean and LS mean difference between Qutenza and pregabalin and its corresponding 95% CI are derived using an analysis of covariance (ANCOVA) model adjusted for gender, pooled country and baseline.
    Comparison groups
    Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated] v Qutenza [Capsaicin (8%) high-concentration patch]
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.4
    Statistical analysis title
    		 Numeric Pain Rating Scale (NPRS) Percent Change
    Statistical analysis description
    The LS mean and LS mean difference between Qutenza and pregabalin and its corresponding 95% CI are derived using an ANCOVA model adjusted for gender, pooled country and baseline.
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    557
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -9.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 -5.2

    Secondary: Time to onset of pain relief (in days) as assessed by at least a 30% change in “average pain for the past 24 hours” Numeric Pain Rating Scale (NPRS) score (FAS)

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    End point title
    		 Time to onset of pain relief (in days) as assessed by at least a 30% change in “average pain for the past 24 hours” Numeric Pain Rating Scale (NPRS) score (FAS)
    End point description
    Time to onset of pain relief was assessed using the analysis of the time to ≥ 30% change (for 3 consecutive days) in “average pain for the past 24 hours” NPRS score. Onset date of pain relief is the date of the first questionnaire recorded with a 30% change. The Time to Onset is derived as Onset Date - Baseline Date + 1 Day. Hazard ratio was estimated using a Cox Model with country (pooled), gender and "average pain for the last 24 hours" NPRS score at baseline as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1 (Day 7), Week 2 (Day 14), Week 4 (Day 29), Week 6 (Day 43), and Week 8 (Day 57) .
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number of Patients
    number (not applicable)
        Day 7 [Number of Patients with Events]
    141
    64
        Day 14 [Number of Patients with Events]
    170
    107
        Day 29 [Number of Patients with Events]
    185
    136
        Day 43 [Number of Patients with Events]
    186
    147
        Day 57 [Number of Patients with Events]
    189
    158
    Statistical analysis title
    		 Time to Onset of Pain Relief
    Statistical analysis description
    Time to onset of pain relief was assessed using the analysis of the time to ≥ 30% change (for 3 consecutive days) in “average pain for the past 24 hours” NPRS score. Time to onset of pain relief was provided by the Cox model, adjusted on country, gender and NPRS score at baseline.
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.35
         upper limit
    		 2.08

    Secondary: Overall patient status using Patient Global Impression of Change (PGIC) questionnaire at Week 4 and Week 8 (FAS)

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    End point title
    		 Overall patient status using Patient Global Impression of Change (PGIC) questionnaire at Week 4 and Week 8 (FAS)
    End point description
    Difference between Qutenza and pregabalin for counts by category were completed using a Cochran-Mantel-Haenszel test. The Patient Global Impression of Change (PGIC) scores ranged from 1 = Very Much Improved to 7 = Very Much Worse. Full Analysis Set (FAS) was used for data analysis and Last Observation Carried Forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 8 End of Study (LOCF)
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number of Patients
    number (not applicable)
        Week 4 [Very Much Improved]
    21
    12
        Week 4 [Much Improved]
    110
    104
        Week 4 [Minimally Improved]
    74
    73
        Week 4 [No Change]
    52
    36
        Week 4 [Minimally Worse]
    10
    8
        Week 4 [Much Worse]
    1
    6
        Week 4 [Very Much Worse]
    0
    0
        Week 8 [Very Much Improved]
    50
    40
        Week 8 [Much Improved]
    94
    83
        Week 8 [Minimally Improved]
    67
    77
        Week 8 [No Change]
    53
    40
        Week 8 [Minimally Worse]
    6
    14
        Week 8 [Much Worse]
    6
    7
        Week 8 [Very Much Worse]
    2
    2
    No statistical analyses for this end point

    Secondary: Change in the Medical Outcomes Study (MOS) 6-item Cognitive Functioning Scale from Baseline to Week 8 (FAS)

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    End point title
    		 Change in the Medical Outcomes Study (MOS) 6-item Cognitive Functioning Scale from Baseline to Week 8 (FAS)
    End point description
    The MOS Cognitive Functioning Scale is a patient reported outcome instrument which measures a range of less severe, day-to-day problems in 6 aspects of cognitive functioning, including reasoning, concentration and thinking, confusion, memory, attention and psychomotor.The MOS 6-item Cognitive Functioning Scale absolute values are presented by treatment arm for the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number
    arithmetic mean (standard deviation)
        Percent Change from Baseline [N=276; N=274]
    12.4 ( 27.27 )
    6.9 ( 54.23 )
        Absolute Change from Baseline [N=276; N=274]
    4 ( 8.47 )
    0.5 ( 10.79 )
    Statistical analysis title
    		 Percent Change (MOS) Cognitive Function
    Comparison groups
    Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated] v Qutenza [Capsaicin (8%) high-concentration patch]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 15.1
    Statistical analysis title
    		 Absolute Change (MOS) Cognitive Function
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 5.7

    Secondary: Medical Outcomes Study (MOS) – Sleep Scale from Baseline to Week 4 and Week 8 (FAS)

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    End point title
    		 Medical Outcomes Study (MOS) – Sleep Scale from Baseline to Week 4 and Week 8 (FAS)
    End point description
    Disturbed sleep is prevalent in people with chronic pain, and its assessment is also important in chronic pain trials. The MOS Sleep Scale measures 6 dimensions of sleep, including initiation, maintenance (e.g., staying asleep), quantity, adequacy, somnolence (e.g.,drowsiness) and respiratory impairments (e.g., shortness of breath, snoring). Disturbed sleep has a major impact on Quality of Life (QoL) and is often a common symptom of many other chronic conditions, such as neuropathic pain. The reliability and validity of the MOS Sleep Scale have been evaluated in a number of disease areas, including neuropathic pain. Patients completed the MOS Sleep Scale at Baseline Visit, Week 4 Visit (Visit 4) and End of Treatment (EOT).
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 4 and 8
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number
    arithmetic mean (standard deviation)
        Week 4 [Absolute Change N=263; N=239]
    4.3 ( 8.75 )
    6.4 ( 8.76 )
        Week 4 [Percent Change N=263; N=239]
    12.3 ( 24.6 )
    17.6 ( 25.43 )
        Week 8/EoS [Absolute Change N=257; N= 244]
    5.1 ( 8.88 )
    6.2 ( 8.79 )
        Week 8/EoS [Percent Change N=257; N=244]
    14 ( 25.45 )
    16.5 ( 24.41 )
        Week 8/EoS BOCF [Absolute Change N=276; N=273]
    4.7 ( 8.66 )
    5.5 ( 8.52 )
        Week 8/EoS BOCF [Percent Change N=276; N=273]
    13 ( 24.81 )
    14.7 ( 23.63 )
    No statistical analyses for this end point

    Secondary: Change in the Euroqol-5 dimensions (EQ-5D-5L) total score from Baseline to Week 8 (FAS)

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    End point title
    		 Change in the Euroqol-5 dimensions (EQ-5D-5L) total score from Baseline to Week 8 (FAS)
    End point description
    The EQ-5D-5L was used as a measure of respondents’ Health-related quality of life (HRQoL) and health status. The EQ-5D-5L provides a simple descriptive profile and a single index value for health status. The EQ-5D-5L patient-rated questionnaire includes a visual analog scale (VAS), which records the respondent's patient-rated health status on a graduated scale (0 to 100), with higher scores for higher HRQoL. It also includes the EQ-5D-5L descriptive system, which comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The responses record 5 levels of severity (i.e., no problems/slight problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D dimension.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8 /EoS (BOCF).
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number
    arithmetic mean (standard deviation)
        Percent Change [N=275; N=272]
    26.5 ( 62.24 )
    20.4 ( 47.09 )
        Absolute Change [N=276; N=272]
    9.9 ( 19.57 )
    8.1 ( 18.83 )
    Statistical analysis title
    		 Percent Change from Baseline (HRQoL) EQ-5D-5L
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    11.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.9
         upper limit
    		 19.2
    Statistical analysis title
    		 Absolute Change from Baseline (HRQoL) EQ-5D
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 5.9

    Secondary: Treatment Satisfaction for Medication (FAS)

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    End point title
    		 Treatment Satisfaction for Medication (FAS)
    End point description
    Endpoint was assessed by TSQM evaluating proportion of patients who discontinued study drug or withdrew due to lack of efficacy or tolerability, or their willingness to continue treatment. The LS mean and LS difference of means between Qutenza and pregabalin and corresponding 95% CI were derived using an ANCOVA model adjusted for gender and pooled country. Factor Score = [(Sum of Obtained Score - Sum of Lowest Possible Score)/ Possible Sum Score Range] x 100, ranging from 0 to 100.
    End point type
    Secondary
    End point timeframe
    Week 8 and Week 12
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number
    arithmetic mean (standard deviation)
        Week 4 [TSQM Scale: Effectiveness]
    57.7 ( 24.59 )
    57.8 ( 20.15 )
        Week 8 (LOCF)[TSQM Scale: Effectiveness]
    61.5 ( 25.57 )
    57.5 ( 23.14 )
        Week 4 [TSQM Scale: Side effects]
    95.6 ( 13.81 )
    80.3 ( 27.32 )
        Week 8 (LOCF) [TSQM Scale: Side effects]
    97 ( 12.27 )
    76.3 ( 31.19 )
        Week 4 [TSQM Scale: Convenience]
    71.7 ( 20.08 )
    74.5 ( 16.24 )
        Week 8 (LOCF) [TSQM Scale: Convenience]
    72.8 ( 20.52 )
    73.6 ( 17.46 )
        Week 4 [TSQM Scale: Global Satisfaction]
    60.7 ( 27.06 )
    58.5 ( 22.53 )
        WEek 8 (LOCF) TSQM Scale: Global Satisfaction
    62.6 ( 29.02 )
    56.1 ( 26.9 )
    No statistical analyses for this end point

    Secondary: Time to reach optimal maintenance dose for Pregabalin (Days) (FAS)

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    End point title
    		 Time to reach optimal maintenance dose for Pregabalin (Days) (FAS) [7]
    End point description
    Patients who withdrew before reaching the maintenance dose were censored at their last available visit date. The time to optimal maintenance dose was derived as the date when Optimal Maintenance Dose was reached - Baseline Date + 1 Day. Optimal Maintenance Dose is defined as the last dose collected and Date Optimal Maintenance Dose reached is the start of the Interval of the Optimal Maintenance Dose.
    End point type
    Secondary
    End point timeframe
    VIsit (Week 1; [Days: 7]), (Week 2; [Days: 14]), (Week 4 [Days 29]), (Week 6 [Days 43]),(Week 8 [Days 57])
    Notes
    [7] - 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: The endpoint measures optimal maintenance dose for pregabalin only, which is why qutenza arm was excluded from the statistics report for this endpoint.
    End point values
    		 Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    277
    Units: Number of Patients
    number (not applicable)
        Week 1 [Day 7]
    10
        Week 2 [Day 14]
    60
        Week 4 [Day 29]
    216
        Week 6 [Day 43]
    248
        Week 8 [Day 57]
    248
    No statistical analyses for this end point

    Secondary: Resource use (number of contacts with health professionals)

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    End point title
    		 Resource use (number of contacts with health professionals)
    End point description
    Details of healthcare resource use (number of contacts with a healthcare professional both related to neuropathic pain and for other causes) were collected at each visit during the study.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment [EOT}
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number
    arithmetic mean (standard deviation)
        Visits related to neuropathic pain[Baseline]
    0.1 ( 0.61 )
    0.2 ( 0.59 )
        Visits related to neuropathic pain[Week 2]
    0.1 ( 0.41 )
    0.1 ( 0.62 )
        Visits related to neuropathic pain[Week 4]
    0.1 ( 0.77 )
    0.1 ( 0.68 )
        Visits related to neuropathic pain[Week 8]
    0.1 ( 0.52 )
    0.1 ( 0.72 )
        Visits related to neuropathic pain[During Study]
    0.4 ( 1.76 )
    0.5 ( 2.04 )
        Visits due to other causes[Baseline]
    0.1 ( 0.62 )
    0.2 ( 0.47 )
        Visits due to other causes[Week 2]
    0.3 ( 0.78 )
    0.3 ( 0.76 )
        Visits due to other causes[Week 4]
    0.2 ( 0.62 )
    0.2 ( 0.56 )
        Visits due to other causes[Week 8]
    0.4 ( 0.93 )
    0.3 ( 0.76 )
        Visits due to other causes[During Study]
    1.1 ( 1.97 )
    0.9 ( 1.68 )
    No statistical analyses for this end point

    Secondary: Tolerability (FAS)

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    End point title
    		 Tolerability (FAS)
    End point description
    The tolerability of treatment was assessed using Adverse Drug Reaction (ADRs) reported by patients in each arm. To increase the sensitivity of Adverse Events (AEs) collection and to limit recall bias on behalf of the patient, patients were asked to assess tolerability between visits, via self-report. In a patient reported outcome, terms such as “adverse event” were not appropriate. Instead, patients were asked open questions as to whether they have any health-related concerns or complaints and the number of complaints. Patients were asked to rate severity as follows; Mild (You could perform your normal daily activities), Moderate (You were limited in performing your normal daily activities) and Severe (You were not able to perform your daily activities).
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment [EOT]
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number of patients
    number (not applicable)
        Patients without TEAEs
    72
    100
        Patients without drug-related TEAEs
    109
    126
        Patients without moderate/severe TEAEs
    135
    153
        Patients without drug-related moderate/severe TEAE
    174
    173
        Patients without severe TEAEs
    226
    229
        Patients without severe drug-related TEAEs
    247
    243
    No statistical analyses for this end point

    Secondary: Change in intensity and area of allodynia from Baseline to Week 8

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    End point title
    		 Change in intensity and area of allodynia from Baseline to Week 8
    End point description
    The area(s) of dynamic mechanical allodynia was mapped with the patient in a comfortable position, as for assessment of the painful area. The intensity of pain associated with the allodynia was rated by the patient using a numeric rating scale.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment (EOT)
    End point values
    		 Qutenza [Capsaicin (8%) high-concentration patch] Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects analysed
    282
    277
    Units: Number
    arithmetic mean (standard deviation)
        Intensity[Absolute change fromBaselineN=282;N=276]
    -3 ( 3.07 )
    -2.3 ( 2.68 )
        Intensity[Percent change from BaselineN=254;N=238]
    -48.2 ( 44.15 )
    -38.2 ( 41.36 )
        Area cm2[Absolute change from BaselineN=282;N=273]
    -101 ( 177.32 )
    -69.7 ( 215.56 )
        Area cm2[Percent change from BaselineN=255;N=235]
    -43.6 ( 93.46 )
    -33.6 ( 64.02 )
    Statistical analysis title
    		 Intensity Absolute change from Baseline
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.2
    Statistical analysis title
    		 Intensity Percent change from Baseline
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference)
    Point estimate
    -10.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.2
         upper limit
    		 -3.5
    Statistical analysis title
    		 Area (cm2) Absolute change from Baseline
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference)
    Point estimate
    -30.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.5
         upper limit
    		 -2.7
    Statistical analysis title
    		 Area (cm2) Percent change from Baseline
    Comparison groups
    Qutenza [Capsaicin (8%) high-concentration patch] v Pregabalin [Oral Hard 75 mg Capsule Up-titrated as tolerated]
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    -10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.3
         upper limit
    		 2.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for Treatment-Emergent Adverse Event (TEAE) was up to 30 days following the last treatment (follow-up window).
    Adverse event reporting additional description
    All safety analyses was conducted on the Safety Analysis Set (SAF) data, and it included all patients who have received the study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Pregabalin [oral hard 75 mg capsules]
    Reporting group description
    		 -

    Reporting group title
    Qutenza [Capsaicin (8%) high-concentration patch]
    Reporting group description
    		 -

    Serious adverse events
    		 Pregabalin [oral hard 75 mg capsules] Qutenza [Capsaicin (8%) high-concentration patch]
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 277 (2.53%)
    10 / 282 (3.55%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incorrect drug administration duration
    Additional description: In the course of the study there was 1 patient who had a patch application with a duration of 60 mins to the feet, which was recorded as an SAE (incorrect drug administration duration), although there were no clinical consequences.
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Wegener's granulomatosis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (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
    Complex regional pain syndrome
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Application site burn
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Swollen tongue
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Pregabalin [oral hard 75 mg capsules] Qutenza [Capsaicin (8%) high-concentration patch]
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    176 / 277 (63.54%)
    208 / 282 (73.76%)
    Investigations
    Weight increased
         subjects affected / exposed
    17 / 277 (6.14%)
    0 / 282 (0.00%)
         occurrences all number
    17
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    51 / 277 (18.41%)
    37 / 282 (13.12%)
         occurrences all number
    85
    66
    Dizziness
         subjects affected / exposed
    54 / 277 (19.49%)
    7 / 282 (2.48%)
         occurrences all number
    108
    7
    Burning sensation
         subjects affected / exposed
    1 / 277 (0.36%)
    45 / 282 (15.96%)
         occurrences all number
    1
    50
    Somnolence
         subjects affected / exposed
    43 / 277 (15.52%)
    2 / 282 (0.71%)
         occurrences all number
    67
    4
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    0 / 277 (0.00%)
    67 / 282 (23.76%)
         occurrences all number
    0
    71
    Pain
         subjects affected / exposed
    7 / 277 (2.53%)
    18 / 282 (6.38%)
         occurrences all number
    8
    28
    Application site erythema
         subjects affected / exposed
    0 / 277 (0.00%)
    25 / 282 (8.87%)
         occurrences all number
    0
    25
    Oedema peripheral
         subjects affected / exposed
    17 / 277 (6.14%)
    3 / 282 (1.06%)
         occurrences all number
    32
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    14 / 277 (5.05%)
    1 / 282 (0.35%)
         occurrences all number
    16
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    35 / 277 (12.64%)
    14 / 282 (4.96%)
         occurrences all number
    48
    20
    Abdominal pain upper
         subjects affected / exposed
    15 / 277 (5.42%)
    9 / 282 (3.19%)
         occurrences all number
    26
    10
    Constipation
         subjects affected / exposed
    14 / 277 (5.05%)
    2 / 282 (0.71%)
         occurrences all number
    19
    2
    Dry mouth
         subjects affected / exposed
    14 / 277 (5.05%)
    0 / 282 (0.00%)
         occurrences all number
    15
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 277 (0.36%)
    59 / 282 (20.92%)
         occurrences all number
    1
    60
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    9 / 277 (3.25%)
    15 / 282 (5.32%)
         occurrences all number
    10
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2012
    The first amendment was the only substantial amendment, prior to the study initiation date, which detailed: ● Revision of the primary endpoint ● Introduction of an Independent Data Review Board (IDRB) ● Definition of clinically significant change in pregabalin dosing between Week 5 and Week 8 ● Definition of clinically significant change in QUTENZA dosing ● Assessment of allodynia at the Screening Visit ● Addition of an “Identification of Painful Area(s)” at Visit 5 (Week 8/EoS Visit) ● Permitted concomitant medications ● A clarification within the AE section that detailed that “Lack of efficacy” was not to be recorded as an AE ● A change to the pregabalin capsule count (to be collected on paper diary rather than electronic diary) ● The discontinuation of pregabalin ● A correction of the MOS Cog Scale, MOS Sleep Scale and NPRS versions ● A correction of NPRS pain score recording time for patients within the QUTENZA arm ● Minor administrative changes and change of study manager.

    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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