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    Clinical Trial Results:
    An Early Phase Development, Partly Blinded, Positive and Vehicle Controlled, Randomised, Non-inferiority Investigation of the Pharmacokinetics, Safety and Efficacy of BB2603 Cutaneous Hand-Pump Spray versus Lamisil® Spray and versus BB2603 Vehicle Hand-Pump Spray in Subjects with Onychomycosis and associated Tinea Pedis.

    Summary
    EudraCT number
    2016-001242-25
    Trial protocol
    DE  
    Global end of trial date
    13 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Aug 2019
    First version publication date
    23 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BBT120126032001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Blueberry Therapeutics Ltd
    Sponsor organisation address
    Mereside, Alderley Park, Congleton Road,Nether Alderley, Macclesfield, Cheshire, United Kingdom, SK10 4TG
    Public contact
    Medical Officer, Blueberry Therapeutics Ltd, +44 1625238776, info@blueberrytherapeutics.com
    Scientific contact
    Medical Officer, Blueberry Therapeutics Ltd, +44 1625238776, info@blueberrytherapeutics.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
    13 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the systemic exposure of the active pharmaceutical ingredient terbinafine after treatment with topical BB2603 cutaneous pump spray in subjects with onychomycosis (OM) and associated tinea pedis (TP) compared to Lamisil® Spray in Part 1 of the study and BB2603 vehicle control spray in Part 2 of the study.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki 1996 and that are consistent with International Conference on Harmonisation/Good Clinical Practice as per commission directive 2005/28/EC, and in accordance with the national laws and regulations of Germany where this study was conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Mar 2017
    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
    Germany: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    35
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This phase 1/2 prospective, partly blinded, positive and vehicle controlled, single site study in Germany included a two-part screening visit, a 28-day initial treatment period followed by a 14-day dose free period (Part 1). Eligible subjects then progressed to Part 2 of the study for long term dosing for up to a further 48 weeks.

    Pre-assignment
    Screening details
    The first screening visit included a clinical and polymerase chain reaction diagnosis of OM in at least one toenail with OM severity index (OSI) score of 1 to 15, and a clinical and potassium hydroxide wet mount microscopy (KOH) diagnosis of associated TP. Eligible subjects were invited to a second screening visit for all other assessments.

    Period 1
    Period 1 title
    Part 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    This part of study was performed in a blinded manner for the BB2603 cutaneous pump spray and BB2603 vehicle spray groups. The study was open-label for Lamisil spray group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BB2603 Cutaneous Pump Spray (Part 1)
    Arm description
    BB2603 cutaneous pump spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (end of treatment [EOT] for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the Test of Cure [TOC] visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing).
    Arm type
    Experimental

    Investigational medicinal product name
    BB2603 cutaneous pump spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous spray, solution
    Routes of administration
    Topical use
    Dosage and administration details
    BB2603 cutaneous pump spray contains 0.01% terbinafine, 0.03% polyhexanide, 20% ethanol and water. BB2603 cutaneous pump spray was applied as 10 sprays (1 millilitre [ml]) per foot/leg once daily giving a total daily dose of 100 microgram (μg) per foot/leg (a total of 200 μg terbinafine/day for the first 28 days). The footwear and inside the shoes were also sprayed.

    Arm title
    Lamisil Spray (Part 1)
    Arm description
    Lamisil spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (EOT for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the TOC visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing) and were then assigned to the Part 2 BB2603 vehicle control spray group.
    Arm type
    Active comparator

    Investigational medicinal product name
    Lamisil spray
    Investigational medicinal product code
    Other name
    Terbinafine 1% Topical Spray
    Pharmaceutical forms
    Cutaneous spray, solution
    Routes of administration
    Topical use
    Dosage and administration details
    Lamisil spray contains 1% terbinafine. Lamisil spray was applied as 10 sprays (1 ml) per foot/leg once daily giving a total daily dose of 20 milligrams (mg) terbinafine/day for the first 28 days.

    Arm title
    BB2603 Vehicle Control Spray (Part 1)
    Arm description
    BB2603 vehicle control spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (EOT for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the TOC visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing).
    Arm type
    Experimental

    Investigational medicinal product name
    BB2603 vehicle control spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous spray, solution
    Routes of administration
    Topical use
    Dosage and administration details
    BB2603 vehicle control spray contains 0.03% polyhexanide, 20% ethanol and water. BB2603 vehicle control spray was applied as 10 sprays (1 mL) per foot/leg once daily. The footwear and inside the shoes were also sprayed.

    Number of subjects in period 1
    BB2603 Cutaneous Pump Spray (Part 1) Lamisil Spray (Part 1) BB2603 Vehicle Control Spray (Part 1)
    Started
    31
    10
    5
    Completed
    31
    10
    5
    Period 2
    Period 2 title
    Part 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BB2603 Cutaneous Pump Spray (Part 2)
    Arm description
    BB2603 cutaneous pump spray was applied once daily for up to 48 weeks. The final follow up (FFU) visit occurred at Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    BB2603 cutaneous pump spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous spray, solution
    Routes of administration
    Topical use
    Dosage and administration details
    BB2603 cutaneous pump spray contains 0.01% terbinafine, 0.03% polyhexanide, 20% ethanol and water. BB2603 pump spray was applied as 5 sprays (0.5 ml) per foot once daily giving a total daily dose of 50 μg per foot (a total of 100 μg terbinafine per day for 48 weeks). The footwear and inside the shoes were also sprayed.

    Arm title
    BB2603 Vehicle Control Spray (Part 2)
    Arm description
    Subjects from the Lamisil spray group in Part 1, joined the BB2603 vehicle control spray group for Part 2. BB2603 vehicle control spray was applied once daily for up to 48 weeks. The FFU visit occurred at Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    BB2603 vehicle control spray
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous spray, solution
    Routes of administration
    Topical use
    Dosage and administration details
    BB2603 vehicle control spray contains 0.03% polyhexanide, 20% ethanol and water. BB2603 vehicle control spray was applied as 5 sprays (0.5 mL) per foot once daily. The footwear and inside the shoes were also sprayed.

    Number of subjects in period 2
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Started
    31
    15
    Completed
    20
    10
    Not completed
    11
    5
         No target nail to evaluate
    1
    -
         OSI stopping criterion fulfilled
    10
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BB2603 Cutaneous Pump Spray (Part 1)
    Reporting group description
    BB2603 cutaneous pump spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (end of treatment [EOT] for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the Test of Cure [TOC] visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing).

    Reporting group title
    Lamisil Spray (Part 1)
    Reporting group description
    Lamisil spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (EOT for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the TOC visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing) and were then assigned to the Part 2 BB2603 vehicle control spray group.

    Reporting group title
    BB2603 Vehicle Control Spray (Part 1)
    Reporting group description
    BB2603 vehicle control spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (EOT for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the TOC visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing).

    Reporting group values
    BB2603 Cutaneous Pump Spray (Part 1) Lamisil Spray (Part 1) BB2603 Vehicle Control Spray (Part 1) Total
    Number of subjects
    31 10 5 46
    Age categorical
    Units: Subjects
        18-45 years
    10 2 1 13
        46-64 years
    14 7 1 22
        65-74 years
    5 1 3 9
        75-90 years
    2 0 0 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.9 ± 14.35 52.0 ± 13.06 60.6 ± 12.12 -
    Gender categorical
    Units: Subjects
        Female
    13 2 0 15
        Male
    18 8 5 31
    Race
    Units: Subjects
        Asian
    1 0 0 1
        Mixed
    1 0 0 1
        White
    29 10 5 44

    End points

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    End points reporting groups
    Reporting group title
    BB2603 Cutaneous Pump Spray (Part 1)
    Reporting group description
    BB2603 cutaneous pump spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (end of treatment [EOT] for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the Test of Cure [TOC] visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing).

    Reporting group title
    Lamisil Spray (Part 1)
    Reporting group description
    Lamisil spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (EOT for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the TOC visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing) and were then assigned to the Part 2 BB2603 vehicle control spray group.

    Reporting group title
    BB2603 Vehicle Control Spray (Part 1)
    Reporting group description
    BB2603 vehicle control spray was applied once daily for 28 consecutive days. All OM and TP lesions on both feet were treated but each subject had target areas identified: the largest and worst nail for OM and the most severe lesion for TP. At Day 28 (EOT for Part 1), subjects had a 14-day dosing break before returning on Day 42 (the TOC visit). Subjects who completed all assessments at TOC had a skin patch sensitisation test (Day 42 to 46). Subjects who completed Day 46 with no significant signs of sensitisation, local intolerability/irritation or significant systemic exposure or safety issues progressed to Part 2 of the study (re-start of dosing).
    Reporting group title
    BB2603 Cutaneous Pump Spray (Part 2)
    Reporting group description
    BB2603 cutaneous pump spray was applied once daily for up to 48 weeks. The final follow up (FFU) visit occurred at Week 52.

    Reporting group title
    BB2603 Vehicle Control Spray (Part 2)
    Reporting group description
    Subjects from the Lamisil spray group in Part 1, joined the BB2603 vehicle control spray group for Part 2. BB2603 vehicle control spray was applied once daily for up to 48 weeks. The FFU visit occurred at Week 52.

    Primary: Concentration of Terbinafine in Plasma Over Time- Part 1

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    End point title
    Concentration of Terbinafine in Plasma Over Time- Part 1 [1]
    End point description
    Blood samples were taken at Day 1 (baseline), at pre-dose (T0), 1 hour (hr), 2 hr, 4 hr, 8 hr, 12 hr post-dose and then each study visit to determine plasma terbinafine levels in all subjects. Where the level of terbinafine in plasma was below the level of quantification (LoQ), the LoQ of 500 nanograms/litre (ng/L), was reported. The concentration of terbinafine in plasma for all subjects in the pharmacokinetic (PK) analysis population is presented at each time point in Part 1. The PK analysis population consisted of all subjects who received at least one dose of treatment and had adequate sampling to calculate PK parameters.
    End point type
    Primary
    End point timeframe
    Part 1: Day 1 (T0, 1 ,2 , 4 , 8 , 12 hr), followed by Days 2, 3, 4, 5, 6, 7, 14, 21, 28 and 42
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As so many of the results were below the LoQ, no comparative analyses were performed.
    End point values
    BB2603 Cutaneous Pump Spray (Part 1) Lamisil Spray (Part 1) BB2603 Vehicle Control Spray (Part 1)
    Number of subjects analysed
    31
    10
    5
    Units: ng/L
    geometric mean (geometric coefficient of variation)
        Day 1/T0
    500.0 ± 0.0
    647.9 ± 97.84
    500.0 ± 0.0
        Day 1/1 hr
    500.0 ± 0.0
    629.1 ± 83.32
    500.0 ± 0.0
        Day 1/2 hr
    500.0 ± 0.0
    647.1 ± 97.16
    500.0 ± 0.0
        Day 1/4 hr
    500.0 ± 0.0
    655.0 ± 103.62
    500.0 ± 0.0
        Day 1/8 hr
    500.0 ± 0.0
    673.3 ± 87.92
    500.0 ± 0.0
        Day 1/12 hr
    500.0 ± 0.0
    691.4 ± 101.00
    500.0 ± 0.0
        Day 2
    500.0 ± 0.0
    705.6 ± 96.55
    500.0 ± 0.0
        Day 3
    500.0 ± 0.0
    758.0 ± 91.93
    500.0 ± 0.0
        Day 4
    500.0 ± 0.0
    766.6 ± 97.28
    500.0 ± 0.0
        Day 5
    500.0 ± 0.0
    810.7 ± 95.14
    500.0 ± 0.0
        Day 6
    500.0 ± 0.0
    832.4 ± 97.72
    500.0 ± 0.0
        Day 7
    500.0 ± 0.0
    876.8 ± 102.12
    500.0 ± 0.0
        Day 14
    500.0 ± 0.0
    802.7 ± 102.50
    500.0 ± 0.0
        Day 21
    500.0 ± 0.0
    858.9 ± 81.07
    500.0 ± 0.0
        Day 28
    500.0 ± 0.0
    820.2 ± 60.64
    500.0 ± 0.0
        Day 42
    500.0 ± 0.0
    587.5 ± 54.47
    500.0 ± 0.0
    No statistical analyses for this end point

    Primary: Concentration of Terbinafine in Plasma Over Time- Part 2

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    End point title
    Concentration of Terbinafine in Plasma Over Time- Part 2 [2]
    End point description
    Blood samples were taken at each study visit in Part 2 to determine plasma terbinafine levels in all subjects. Where the level of terbinafine in plasma was below the LoQ, the LoQ of 500 ng/L, was reported. The concentration of terbinafine in plasma for all subjects in the PK analysis population is presented at each time point in Part 2. The PK analysis population consisted of all subjects who received at least one dose of treatment and had adequate sampling to calculate PK parameters.
    End point type
    Primary
    End point timeframe
    Part 2: Day 46/Week 0, Weeks 4, 8, 12, 16, 20, 24, 36, 48 and 52
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As so many of the results were below the LoQ, no comparative analyses were performed.
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    31 [3]
    15 [4]
    Units: ng/L
    geometric mean (geometric coefficient of variation)
        Week 0
    500.0 ± 0.0
    537.1 ± 28.26
        Week 4
    500.0 ± 0.0
    517.2 ± 13.17
        Week 8
    500.0 ± 0.0
    500.0 ± 0.0
        Week 12
    500.0 ± 0.0
    500.0 ± 0.0
        Week 16
    500.0 ± 0.0
    500.0 ± 0.0
        Week 20
    500.0 ± 0.0
    500.0 ± 0.0
        Week 24
    500.0 ± 0.0
    500.0 ± 0.0
        Week 36
    500.0 ± 0.0
    500.0 ± 0.0
        Week 48
    500.0 ± 0.0
    500.0 ± 0.0
        Week 52
    500.0 ± 0.0
    500.0 ± 0.0
    Notes
    [3] - Except: Weeks 4-8, n=30; Week 16, n=29; Week 20, n=27; Week 24, n=26; Week 36, n=24; Week 48, n=20
    [4] - Except: Week 24, n=14; Week 36, n=12; Week 48, n=10
    No statistical analyses for this end point

    Primary: Concentration of Terbinafine in Nail Samples Over Time - Part 1

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    End point title
    Concentration of Terbinafine in Nail Samples Over Time - Part 1 [5]
    End point description
    Nail clippings and scrapings were collected from the target OM lesions to assess localised terbinafine exposure. Samples were collected from subjects at baseline (Day 1/T0) and Day 28 from Part 1 of the study and analysed for terbinafine concentration. Where the level of terbinafine was below the LoQ, the LoQ of 0.0040 mg/L, was reported. The concentration of terabinafine in nail samples for all subjects in the PK analysis population is presented at each time point in Part 1. The PK analysis population consisted of all subjects who received at least one dose of treatment and had adequate sampling to calculate PK parameters.
    End point type
    Primary
    End point timeframe
    Part 1: Day 1 (T0) and Day 28
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As so many of the results were below the LoQ, no comparative analyses were performed.
    End point values
    BB2603 Cutaneous Pump Spray (Part 1) Lamisil Spray (Part 1) BB2603 Vehicle Control Spray (Part 1)
    Number of subjects analysed
    31
    10
    5
    Units: mg/L
    geometric mean (geometric coefficient of variation)
        Clippings Day 1
    0.0040 ± 0.00000
    0.0135 ± 2229.01504
    0.0040 ± 0.00000
        Clippings Day 28
    0.0500 ± 203.11839
    5.3477 ± 219.81286
    0.0040 ± 0.00000
        Scrapings Day 1
    0.0044 ± 54.06850
    0.0135 ± 1555.46873
    0.0040 ± 0.00000
        Scrapings Day 28
    0.0333 ± 128.45942
    3.4480 ± 531.94940
    0.0040 ± 0.00000
    No statistical analyses for this end point

    Primary: Concentration of Terbinafine in Nail Samples Over Time - Part 2

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    End point title
    Concentration of Terbinafine in Nail Samples Over Time - Part 2 [6]
    End point description
    Nail clippings and scrapings were collected from the target OM lesions to assess localised terbinafine exposure. Samples were collected from subjects at Day 46/Week 0, Weeks 12, 24, 36, 48 and 52 in Part 2 of the study and analysed for terbinafine concentration. Where the level of terbinafine was below the LoQ, the LoQ of 0.0040 mg/L, was reported. The concentration of terbinafine in nail samples for all subjects in the PK analysis population is presented at each time point in Part 2. The PK analysis population consisted of all subjects who received at least one dose of treatment and had adequate sampling to calculate PK parameters.
    End point type
    Primary
    End point timeframe
    Part 2: Day 46/Week 0, Weeks 12, 24, 36, 48 and 52
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As so many of the results were below the LoQ, no comparative analyses were performed.
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    30 [7]
    15 [8]
    Units: mg/L
    geometric mean (geometric coefficient of variation)
        Clippings Week 0
    0.0079 ± 68.93527
    0.0901 ± 3818.58840
        Clippings Week 12
    0.1595 ± 205.04130
    0.0089 ± 751.13565
        Clippings Week 24
    0.2031 ± 138.84601
    0.0068 ± 278.81358
        Clippings Week 36
    0.2271 ± 218.27985
    0.0066 ± 444.83859
        Clippings Week 48
    0.1293 ± 203.63449
    0.0061 ± 219.43656
        Clippings Week 52
    0.0184 ± 472.95252
    0.0051 ± 103.85511
        Scrapings Week 0
    0.0085 ± 88.76985
    0.1019 ± 13858.77514
        Scrapings Week 12
    0.1383 ± 208.66846
    0.0156 ± 920.60044
        Scrapings Week 24
    0.1724 ± 151.96280
    0.0077 ± 499.25629
        Scrapings Week 36
    0.2072 ± 173.65924
    0.0072 ± 363.22453
        Scrapings Week 48
    0.0977 ± 171.84931
    0.0060 ± 196.66150
        Scrapings Week 52
    0.0191 ± 395.25603
    0.0052 ± 96.91706
    Notes
    [7] - Except: Week 12, n=30/29 (clippings/scrapings); Week 24, n=25/26; Week 36, n=23/24 Week 48, n=20/20
    [8] - Except:Week 24, n=14/14 (clippings/scrapings); Week 36, n=12/12; Week 48, n=10/10
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a Clinical TP Cure - Part 1

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    End point title
    Percentage of Subjects with a Clinical TP Cure - Part 1
    End point description
    A target TP area on one foot was identified as the most severe TP lesion and evaluated at the baseline visit and at each subsequent visit in Part 1 of the study. Each of the clinical signs (fissuring/cracking, erythema, maceration and scaling) and symptoms (pruritus and burning/stinging) of TP were scored and documented with photographs. Each score was objectively defined on a 0-3 scale where 0 = none - complete absence of any signs or symptoms, 1 = mild - slight, 2 = moderate definitely present, 3 = severe - marked, intense. The percentage of subjects from the modified intent-to-treat (mITT) population with a clinical TP cure (i.e. no clinical signs or symptoms of TP) at Days 1, 28 and 42 during Part 1 of the study is presented. The mITT population included all randomised subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part 1: Days 1, 28 and 42
    End point values
    BB2603 Cutaneous Pump Spray (Part 1) Lamisil Spray (Part 1) BB2603 Vehicle Control Spray (Part 1)
    Number of subjects analysed
    18
    1
    4
    Units: Percentage of subjects
    number (not applicable)
        Day 1
    0.0
    0.0
    0.0
        Day 28
    5.6
    0.0
    25.0
        Day 42
    11.1
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a Complete TP Cure - Part 1

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    End point title
    Percentage of Subjects with a Complete TP Cure - Part 1
    End point description
    Subjects with no clinical symptoms or signs, a negative KOH wet mount microscopy and a negative culture for dermatophytes were classed as having a complete TP cure. The percentage of subjects in the mITT population with a complete TP cure is presented for Days 1, 28 and 42 in Part 1 of the study. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part1: Days 1, 28 and 42
    End point values
    BB2603 Cutaneous Pump Spray (Part 1) Lamisil Spray (Part 1) BB2603 Vehicle Control Spray (Part 1)
    Number of subjects analysed
    18
    1
    4
    Units: Percentage of subjects
    number (not applicable)
        Day 1
    0.0
    0.0
    0.0
        Day 28
    5.6
    0.0
    0.0
        Day 42
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Median Time to Total Mycological Cure Day - Part 1

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    End point title
    Median Time to Total Mycological Cure Day - Part 1
    End point description
    Skin scrapings for KOH assessment were taken from the target lesion (and other visible lesions) at baseline (Day 1) and each study visit up to Day 42 in Part 1 of the study. Total mycological cure day was defined as the study day on which ≥ 60% of subjects have a negative KOH and time to total mycological cure day was computed using the Kaplan-Meier estimate. Subjects who did not achieve negative KOH were censored on day of last TP assessment. The median time to total mycological cure day is reported for subjects in the mITT population in the BB2603 Cutaneous Pump Spray and Lamisil Spray groups only. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 42
    End point values
    BB2603 Cutaneous Pump Spray (Part 1) Lamisil Spray (Part 1) BB2603 Vehicle Control Spray (Part 1)
    Number of subjects analysed
    17
    1
    0 [9]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    42.0 (15.0 to 70.0)
    46.0 (46.0 to 46.0)
    ( to )
    Notes
    [9] - Total mycological cure day was not reached for this group as <60% of subjects had a negative KOH.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with TP Recurrence - Part 2

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    End point title
    Percentage of Subjects with TP Recurrence - Part 2
    End point description
    Recurrence of TP after improvement was defined as some clinical symptoms or signs of TP, assessed using documented photographs, scored on a scale of 0-3 and from skin scrapings (KOH). Recurrence of TP was assessed at the FFU visit in Part 2 and the percentage of subjects (calculated based on the number of subjects with clinical TP cure at Day 28 in Part 1 of the study) is presented.
    End point type
    Secondary
    End point timeframe
    Week 52 in Part 2
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    1 [10]
    1 [11]
    Units: Percentage of Subjects
        number (not applicable)
    100.0
    0.0
    Notes
    [10] - Number of subjects with clinical TP cure at Day 28 in Part 1.
    [11] - Number of subjects with clinical TP cure at Day 28 in Part 1.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with an OM Negative Culture - Part 2

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    End point title
    Percentage of Subjects with an OM Negative Culture - Part 2
    End point description
    OM culture for dermatophytes was assessed at each study visit in Part 2 of the study. The percentage of subjects in the mITT population with no dermatophyte growth in the OM cultures (i.e. OM negative culture) is presented for Weeks 0, 48 and 52 in Part 2 of the study. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part 2: Day 46/Week 0, Weeks 48 and 52
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    18
    5
    Units: Percentage of Subjects
    number (not applicable)
        Week 0
    77.8
    80.0
        Week 48
    33.3
    40.0
        Week 52
    72.2
    40.0
    No statistical analyses for this end point

    Secondary: Mean OSI Total Score - Part 2

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    End point title
    Mean OSI Total Score - Part 2
    End point description
    Clinical OM assessment was made using the OSI at each study visit in Part 2 of the study. The OSI was obtained by multiplying the score for the area of involvement (range, 0-5) by the score for the proximity of disease to the matrix (range, 1-5). Ten points were added for the presence of a longitudinal streak or a patch (dermatophytoma) or for greater than 2mm of subungual hyperkeratosis. Mild OM corresponds to a score of 1-5; moderate OM to a score of 6-15; and severe OM to a score of 16-35. The mean OSI total score is presented for subjects in the mITT population at Weeks 0, 48 and 52 in Part 2 of the study. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part 2: Day 46/Week 0, Weeks 48 and 52
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    18 [12]
    5 [13]
    Units: OSI score
    arithmetic mean (standard deviation)
        Week 0
    8.1 ± 4.39
    4.6 ± 2.97
        Week 48
    6.0 ± 3.20
    5.3 ± 2.99
        Week 52
    8.7 ± 5.12
    5.4 ± 2.61
    Notes
    [12] - Except: Week 48, n=9; Week 52, n=17
    [13] - Except: Week 48, n=4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with an OM Negative Culture for Dermatophytes and an OSI of Zero - Part 2

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    End point title
    Percentage of Subjects with an OM Negative Culture for Dermatophytes and an OSI of Zero - Part 2
    End point description
    The percentage of subjects in the mITT population with an OM negative culture for dermatophytes, combined with an OSI score of zero, is presented for subjects at Weeks 0, 48 and 52 in Part 2 of the study. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part 2: Day 46/Week 0, Weeks 48 and 52
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    18
    5
    Units: Percentage of Subjects
    number (not applicable)
        Week 0
    0.0
    0.0
        Week 48
    0.0
    0.0
        Week 52
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a Partial Cure of OM - Part 2

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    End point title
    Percentage of Subjects with a Partial Cure of OM - Part 2
    End point description
    Partial cure of OM was defined as eradication of dermatophyte infection on cultures from nail scrapings and with less than or equal to 10% of the target nail still with a clinical diagnosis of OM. The percentage of subjects in the mITT population with a partial OM cure at Weeks 0, 48 and 52 of Part 2 of the study is presented. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part 2: Day 46/Week 0, Weeks 48 and 52
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    18
    5
    Units: Percentage of Subjects
    number (not applicable)
        Week 0
    5.6
    0.0
        Week 48
    0.0
    0.0
        Week 52
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with OM Improvement - Part 2

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    End point title
    Percentage of Subjects with OM Improvement - Part 2
    End point description
    OM improvement was defined as eradication of dermatophyte infection on culture from nail scrapings and with a reduction in OSI score by at least 40% from baseline (Day 1). The percentage of subjects in the mITT population with OM improvement at Weeks 0, 48 and 52 in Part 2 of the study is presented. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part 2: Day 46/Week 0, Weeks 48 and 52
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    18
    5
    Units: Percentage of Subjects
    number (not applicable)
        Week 0
    0.0
    0.0
        Week 48
    11.1
    0.0
        Week 52
    5.6
    0.0
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in OSI Score - Part 2

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    End point title
    Mean Change from Baseline in OSI Score - Part 2
    End point description
    The OSI is obtained by multiplying the score for the area of involvement (range, 0-5) by the score for the proximity of disease to the matrix (range, 1-5). Ten points are added for the presence of a longitudinal streak or a patch (dermatophytoma) or for greater than 2mm of subungual hyperkeratosis. Mild OM corresponds to a score of 1-5; moderate OM to a score of 6-15; and severe OM to a score of 16-35. The mean change from baseline (Day 1 in Part 1) in OSI total score at Weeks 0, 48 and 52 in Part 2 of the study is presented for subjects in the mITT population. The mITT population included all subjects who met the important inclusion/exclusion criteria, and, for the TP analysis, had a dermatophyte infection.
    End point type
    Secondary
    End point timeframe
    Part 1: Day 1 and Part 2: Day 46/Week 0, Weeks 48 and 52
    End point values
    BB2603 Cutaneous Pump Spray (Part 2) BB2603 Vehicle Control Spray (Part 2)
    Number of subjects analysed
    16 [14]
    4 [15]
    Units: OSI score
    arithmetic mean (standard deviation)
        Week 0
    1.3 ± 3.13
    0.0 ± 0.00
        Week 48
    -0.8 ± 2.77
    0.0 ± 0.00
        Week 52
    1.1 ± 2.89
    1.0 ± 2.00
    Notes
    [14] - Except: Week 48, n=9; Week 52, n=15
    [15] - Except: Week 48, n=3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) were recorded from baseline (Day 1 in Part 1) until Week 52 (FFU visit in Part 2).
    Adverse event reporting additional description
    TEAEs are reported for the safety population which included all subjects who had at least one dose of study treatment and one subsequent contact with the Investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Part 1: BB2603 Cutaneous Pump Spray
    Reporting group description
    All subjects assigned to the BB2603 Cutaneous Pump Spray group in Part 1 who have had at least one dose of study treatment and one subsequent contact with the Investigator.

    Reporting group title
    Part 1: Lamisil Spray
    Reporting group description
    All subjects assigned to the Lamisil Spray group in Part 1 who have had at least one dose of study treatment and one subsequent contact with the Investigator.

    Reporting group title
    Part 1: BB2603 Vehicle Control Spray
    Reporting group description
    All subjects assigned to the BB2603 Vehicle Control Spray group in Part 1 who have had at least one dose of study treatment and one subsequent contact with the Investigator.

    Reporting group title
    Part 2: BB2603 Cutaneous Pump Spray
    Reporting group description
    All subjects assigned to the BB2603 Cutaneous Pump Spray group in Part 2 who have had at least one dose of study treatment and one subsequent contact with the Investigator.

    Reporting group title
    Part 2: BB2603 Vehicle Control Spray
    Reporting group description
    All subjects assigned to the BB2603 Vehicle Control Spray group in Part 2 who have had at least one dose of study treatment and one subsequent contact with the Investigator.

    Serious adverse events
    Part 1: BB2603 Cutaneous Pump Spray Part 1: Lamisil Spray Part 1: BB2603 Vehicle Control Spray Part 2: BB2603 Cutaneous Pump Spray Part 2: BB2603 Vehicle Control Spray
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Part 1: BB2603 Cutaneous Pump Spray Part 1: Lamisil Spray Part 1: BB2603 Vehicle Control Spray Part 2: BB2603 Cutaneous Pump Spray Part 2: BB2603 Vehicle Control Spray
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 31 (54.84%)
    4 / 10 (40.00%)
    2 / 5 (40.00%)
    18 / 31 (58.06%)
    9 / 15 (60.00%)
    Vascular disorders
    Angiodysplasia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypertensive crisis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Surgical and medical procedures
    Dental care
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Elective surgery
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Endometrial ablation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tooth repair
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Catheter site related reaction
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Limb injury
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 31 (6.45%)
    2 / 15 (13.33%)
         occurrences all number
    2
    0
    0
    2
    2
    Sunburn
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Scratch
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Asthma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 31 (16.13%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    4 / 31 (12.90%)
    0 / 15 (0.00%)
         occurrences all number
    6
    1
    0
    19
    0
    Migraine
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Somnolence
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Skin irritation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    0
    1
    3
    Pain in extremity
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    0
    1
    3
    Musculoskeletal pain
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    4 / 31 (12.90%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    0
    4
    1
    Oral herpes
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Rash pustular
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 31 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Borrelia infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 31 (3.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2017
    Amendment 1 (03 Jan 17) was in response to the deficiency letter to the ethics committee to confirm that safety and PK analyses were to be performed and that both must not have shown any harm to the subjects before Part 2 commenced. It also included confirmation that the data and safety monitoring board must assess the data and confirm that it was safe for the subjects to proceed and confirmation that significant disease progression/tolerability resulted in the subject leaving the study and being given standard medical treatment. This was triggered by the subject or the increase of OSI score ≥2.
    08 Jan 2018
    Amendment 2 (08 January 2018). Clarification that only systemic PK data was to be used during Part 1 for safety review. OSI score was developed and validated to define the severity of OM in 4 categories.The OSI score numerical values were not validated as a staging or prognostic score. In addition, analysis of ongoing data suggested that the OSI score increase of ≥2 was too sensitive to identify clinical worsening. Clarification that the individual subject data was to be reviewed for concomitant medication during the study that might impact safety or efficacy assessment. Clarification added that clinical site team and sponsor remained blinded on a per subject level and that the pharmacy was responsible for keeping all code break envelopes. Sample size for this study was corrected to reflect that sample size is appropriate for testing of the efficacy endpoint of complete TP cure at Day 42 and mycological OM cure at 52 weeks. Statistical section 'efficacy analyses' was updated to allow for further sensitivity analysis. Sample collection procedures were updated and micro lab procedures deleted to reconcile with standard procedures used by the study laboratory.
    13 Aug 2018
    Amendment 3 (23 August 2018). Mycological OM cure definition clarified to what is measured in the study and hence revised to ‘OM negative culture'. Clarification of the term 'complete OM cure' was revised to ‘combined endpoint of negative culture for dermatophytes and an OSI of zero’ since OM KOH was not assessed in Part 2 of the study. Clarification of what was measured at baseline for 'Change from Baseline OSI' endpoint. The photometric OSI score and planimetric assessment were made an exploratory endpoint since the OSI score was not validated to measure and assess treatment response. OSI score used for early withdrawal was to be based on photographic OSI assessment. Clarification that Trichophyton mentagrophytes is also known as Trichophyton mentagrophytes var. interdigitale or Trichophyton interdigitale. Clarification of when the adverse events were to be collected (i.e., the data cut-off date) for the safety analysis. Clarification that OM of the target nail would be assessed clinically using OSI, and also by independent photographic assessment. Inclusion of the Occupational, Environmental and Lifestyle risk factor questionnaire. Stratification by dermatophyte group was replaced with classification by dermatophyte group for clarification.

    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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