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    Clinical Trial Results:
    Randomized, open-label, controlled study on the efficacy of Ciclopoli® (ciclopirox 8% nail lacquer) versus Loceryl® (amorolfine 5% nail lacquer) on the culture conversion to negative in patients with onychomycosis

    Summary
    EudraCT number
    		 2011-003087-70
    Trial protocol
    		 LV  
    Global end of trial date
    27 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2017
    First version publication date
    05 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PM1125
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Polichem S.A.
    Sponsor organisation address
    50, Val Fleuri, Luxembourg, Luxembourg,
    Public contact
    Maurizio Caserini, Polichem S.A., 0041 919864000, maurizio.caserini@polichem.com
    Scientific contact
    Maurizio Caserini, Polichem S.A., 0041 919864000, maurizio.caserini@polichem.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
    04 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Ciclopoli® (ciclopirox 8%, coded as P-3051) water soluble nail lacquer and Loceryl® (amorolfine 5%) water insoluble nail lacquer in the conversion to negative of culture evaluated at week 12. All results data are based on the Intention-to-Treat population (ITT): all randomized patients who received at least one dose of the investigational medicinal product, with baseline evaluation and with at least one post-baseline efficacy measurement, i.e. any post-baseline measurement of primary efficacy variable. N (ITT 12w) = 137; N (ITT 48w) = 120.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization (ICH) Consolidated Guideline on Good Clinical Practice (GCP). Prior to study start, patients received a full explanation of the aims of the study, benefits, potential discomforts and risks of taking part in the study. A written explanation was provided in the study information sheet at the screening visit or before. The written informed consent was then obtained before any study procedure was started.
    Background therapy
    		 -
    Evidence for comparator
    		 No data are available yet on the kinetic of culture conversion to negative of 8% ciclopirox-medicated nail lacquer and of amorolfine 5% nail lacquer in the first three months of treatment. The aim of this phase III study is to evaluate the kinetic of culture conversion to negative of 8% ciclopirox-medicated nail lacquer administered according to Summary of Product Characteristics (SPC) compared to amorolfine administered according to SPC in patients affected by mild-tomoderate, distal sub-ungual onychomycosis of the toenails in the first three, six and twelve treatment months.
    Actual start date of recruitment
    21 Feb 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Latvia: 120
    Worldwide total number of subjects
    137
    EEA total number of subjects
    120
    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)
    121
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with mild-to-moderate distal subungual onychomycosis (without lunula involvement) due to fungal nail pathogens (dermatophytes, white yeasts and/or Scopulariopsis spp. and/or Fusarium spp.) confirmed by the culture affecting at least one big toenail were recruited.

    Pre-assignment
    Screening details
    		 Patients fulfilling the inclusion criteria entered the study and were randomly allocated in a balanced randomisation (1:1 ratio) to one out of the two treatment groups.

    Period 1
    Period 1 title
    Period 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was on two arms with an open label design. The different posology (once a day of P-3051 vs twice a week of amorolfine 5%) had not allowed to design a double-blind study. In order to overcome this limitation, the protocol foresaw to do, at the end of the study, a blind evaluation of pictures and computerized planimetry data by the International Scientific Study Coordinator, who gave an unbiased judgement, of secondary endpoints had been reached for each patient.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Ciclopoli® Nagellack
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ciclopirox 8% nail lacquer
    Investigational medicinal product code
    P-3051
    Other name
    Ciclopoli® Nagellack
    Pharmaceutical forms
    Medicated nail lacquer
    Routes of administration
    Topical use
    Dosage and administration details
    Used batch: Latvia, 9290A (expiry date: 06/2014); Russia, 11160A (expiry date 11/2015). To be applied once a day, according to the approved leaflet.

    Arm title
    		 Group B
    Arm description
    		 Loceryl® Wirkstoffhaltiger Nagellack
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amorolfine 5% nail lacquer
    Investigational medicinal product code
    Other name
    Loceryl® Wirkstoffhaltiger Nagellack
    Pharmaceutical forms
    Medicated nail lacquer
    Routes of administration
    Topical use
    Dosage and administration details
    Used batches: Latvia, 1212212 (expiry date 08/2014); Russia, 2212221 (expiry date 07/2015). To be applied twice a week, according to the approved leaflet.

    Number of subjects in period 1
    		Group A Group B
    Started
    69
    68
    Completed
    64
    67
    Not completed
    5
    1
         Protocol deviation
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Ciclopoli® Nagellack

    Reporting group title
    Group B
    Reporting group description
    		 Loceryl® Wirkstoffhaltiger Nagellack

    Reporting group values
    		 Group A Group B Total
    Number of subjects
    		 69 68 137
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 62 59 121
        From 65-84 years
    		 7 9 16
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.64 ± 11.3 52.91 ± 13.07 -
    Gender categorical
    Units: Subjects
        Female
    		 56 54 110
        Male
    		 13 14 27

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Ciclopoli® Nagellack

    Reporting group title
    Group B
    Reporting group description
    		 Loceryl® Wirkstoffhaltiger Nagellack

    Primary: Conversion to negative of culture evaluated at 12 weeks

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    End point title
    		 Conversion to negative of culture evaluated at 12 weeks
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to Week 12.
    End point values
    		 Group A Group B
    Number of subjects analysed
    69
    68
    Units: number of patients with negative result
    54
    44
    Statistical analysis title
    		 Comparisons between groups at Week 12
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.079
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.136
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.014
         upper limit
    		 0.285
    Notes
    [1] - The comparison between groups at week 12 showed that the difference between the P-3051 group and the amorolfine 5% group was equal to 0.136. The 95% CI of the difference between groups was -0.014 to 0.285, and lied entirely above the pre-specified limit of -9%, thus showing that P-3051 was not inferior to amorolfine 5%. The difference between groups was not statistically significant (P = 0.079).

    Secondary: Conversion to negative of culture evaluated at 4 and 8 weeks

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    End point title
    		 Conversion to negative of culture evaluated at 4 and 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Week 4 and Week 8.
    End point values
    		 Group A Group B
    Number of subjects analysed
    69
    68
    Units: number of patients with negative result
        Week 4
    12
    7
        Week 8
    25
    9
    Statistical analysis title
    		 Comparisons between groups at Week 4
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.229
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.071
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.044
         upper limit
    		 0.186
    Notes
    [2] - The comparison between groups showed that the difference between the P-3051 group and the amorolfine 5% group was equal to 0.071. The 95% CI of the difference between groups was -0.044 to 0.186, thus showing that the difference between groups was not statistically significant (P = 0.229).
    Statistical analysis title
    		 Comparisons between groups at Week 8
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.002
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.091
         upper limit
    		 0.369
    Notes
    [3] - The comparison between groups showed that the difference between the P-3051 group and the amorolfine 5% group was equal to 0.230. The 95% CI of the difference between groups was 0.091 to 0.369, thus showing that the difference between groups was statistically significant (P = 0.002), in favour of the P-3051 group.

    Secondary: Conversion to negative of microscopy

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    End point title
    		 Conversion to negative of microscopy
    End point description
    Conversion to negative of microscopy using Potassium Hydroxide (KOH) preparation.
    End point type
    Secondary
    End point timeframe
    At Week 8 and Week 12.
    End point values
    		 Group A Group B
    Number of subjects analysed
    69
    68
    Units: patients with a negative result
        Week 4
    2
    0
        Week 8
    18
    2
        Week 12
    44
    37
    Statistical analysis title
    		 Comparisons between groups at Week 8
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 = 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.231
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.343
    Notes
    [4] - The results at week 8 showed that conversion to negative of microscopy (KOH) was observed in 18 patients (26.1%) in the P-3051 group and in 2 (2.9%) in the amorolfine 5% group. The comparison between groups showed that the difference between the P-3051 group and the amorolfine 5% group was equal to 0.231. The 95% CI of the difference between groups was 0.120 to 0.343, thus showing that the difference between groups was statistically significant (P = 0.0001), in favour of the P-3051 group.
    Statistical analysis title
    		 Comparisons between groups at Week 12
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 = 0.265
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.094
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.258
    Notes
    [5] - The results at week 12 showed that conversion to negative of microscopy (KOH) was observed in 44 patients (63.8%) in the P-3051 group and in 37 (54.4%) in the amorolfine 5% group. The comparison between groups showed that the difference between the P-3051 group and the amorolfine 5% group was equal to 0.094. The 95% CI of the difference between groups was -0.070 to 0.258, thus showing that the difference between groups was not statistically significant (P = 0.265).

    Secondary: Determination of nail infected area compared to baseline

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    End point title
    		 Determination of nail infected area compared to baseline
    End point description
    Results of percent decrease from baseline of nail infected area by visit.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 4, Week 8 and Week 12.
    End point values
    		 Group A Group B
    Number of subjects analysed
    69
    68
    Units: percent
    arithmetic mean (standard deviation)
        Week 4
    -6.27 ± 14.19
    -7.12 ± 14.54
        Week 8
    -14.94 ± 20.44
    -17.39 ± 21.03
        Week 12
    -30.02 ± 24.99
    -27.17 ± 27.67
    No statistical analyses for this end point

    Secondary: Determination of growth rate of healthy nail

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    End point title
    		 Determination of growth rate of healthy nail
    End point description
    Changes from baseline in healthy area of the target big toenail by visit.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 4, Week 8 and Week 12.
    End point values
    		 Group A Group B
    Number of subjects analysed
    69
    68
    Units: increase of healthy area
    arithmetic mean (standard deviation)
        Week 4
    3.1 ± 7.31
    3.47 ± 6.65
        Week 8
    6.71 ± 9.17
    8 ± 9.56
        Week 12
    12.75 ± 11.27
    12.69 ± 12.97
    No statistical analyses for this end point

    Secondary: Responders rate at week 12

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    End point title
    		 Responders rate at week 12
    End point description
    Patients with conversion to negative of culture and of microscopic KOH examination and with decrease of affected nail area to ≤10% of total.
    End point type
    Secondary
    End point timeframe
    At Week 12.
    End point values
    		 Group A Group B
    Number of subjects analysed
    69
    68
    Units: number of responders
    0
    3
    No statistical analyses for this end point

    Secondary: Complete cure rate at week 12

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    End point title
    		 Complete cure rate at week 12
    End point description
    Complete replacement of the affected nail by new healthy nail, accompanied by conversion to negative of culture and of microscopic KOH examination.
    End point type
    Secondary
    End point timeframe
    At Week 12.
    End point values
    		 Group A Group B
    Number of subjects analysed
    69
    68
    Units: number of patients
    0
    0
    No statistical analyses for this end point

    Secondary: Complete cure rate at week 48

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    End point title
    		 Complete cure rate at week 48
    End point description
    Complete replacement of the affected nail by new healthy nail, accompanied by conversion to negative of culture and of microscopic KOH examination.
    End point type
    Secondary
    End point timeframe
    At Week 48.
    End point values
    		 Group A Group B
    Number of subjects analysed
    60
    60
    Units: number of patients
    21
    7
    Statistical analysis title
    		 Comparison between groups at week 48
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.233
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.088
         upper limit
    		 0.379
    Notes
    [6] - The results at week 48 showed that complete cure was observed in 21 patients (35.0%) in the P- 3051 group and in 7 (11.7%) in the amorolfine 5% group. The comparison between groups showed that the difference between the P-3051 group and the amorolfine 5% group was equal to 0.233. The 95% CI of the difference between groups was 0.088 to 0.379, thus showing that the difference between groups was statistically significant (P < 0.001), in favour of the P-3051 group.

    Secondary: Responders rate at week 48

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    End point title
    		 Responders rate at week 48
    End point description
    Patients with conversion to negative of culture and of microscopic KOH examination and with decrease of affected nail area to ≤10% of total.
    End point type
    Secondary
    End point timeframe
    At Week 48.
    End point values
    		 Group A Group B
    Number of subjects analysed
    60
    60
    Units: number of responders
    35
    16
    Statistical analysis title
    		 Comparison between groups at week 48
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Median difference (net)
    Point estimate
    0.317
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.149
         upper limit
    		 0.484
    Notes
    [7] - The results at week 48 showed that response was observed in 35 patients (58.3%) in the P-3051 group and in 16 (26.7%) in the amorolfine 5% group. The comparison between groups showed that the difference between the P-3051 group and the amorolfine 5% group was equal to 0.317. The 95% CI of the difference between groups was 0.149 to 0.484, thus showing that the difference between groups was statistically significant (P < 0.001), in favour of the P-3051 group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety was monitored throughout the whole study period, from screening to discontinuation visit, by recording any adverse event (AE).
    Adverse event reporting additional description
    AEs are described considering the safety population: all randomized subjects who received at least one dose of the study products.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    P-3051
    Reporting group description
    		 -

    Reporting group title
    Amorolfine 5%
    Reporting group description
    		 -

    Serious adverse events
    		 P-3051 Amorolfine 5%
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 68 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 P-3051 Amorolfine 5%
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 69 (31.88%)
    23 / 68 (33.82%)
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Heat stroke
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    3 / 69 (4.35%)
    1 / 68 (1.47%)
         occurrences all number
    3
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Nail operation
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 69 (11.59%)
    11 / 68 (16.18%)
         occurrences all number
    9
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 68 (2.94%)
         occurrences all number
    1
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 69 (2.90%)
    1 / 68 (1.47%)
         occurrences all number
    2
    1
    Cystitis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Helicobacter gastritis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 68 (2.94%)
         occurrences all number
    1
    2
    Laryngitis
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 69 (0.00%)
    4 / 68 (5.88%)
         occurrences all number
    0
    4
    Rhinitis
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 68 (2.94%)
         occurrences all number
    2
    2
    Tooth abscess
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Sep 2012
    Substantial amendment No. 1 (all sites): At the time of the protocol design, no data of superiority of amorolfine 5% drug versus placebo or non-inferiority versus active comparator, had ever been published. Therefore, the collection of clinical and mycological data after 6 and 12 months of treatment was originally included in the protocol as secondary endpoints. New studies at the end of 2011 presented the results of mycological cure with amorolfine at the end of the treatment period (48 weeks). Therefore these publications made available the results of secondary endpoints scheduled in the study protocol that were unavailable at the time of the protocol writing. In order to focalize the study on the primary end-point of the study (kinetic of culture conversion to negative of 8% ciclopirox-medicated nail lacquer and of amorolfine 5% nail lacquer in the first 3 months of treatment), the protocol was amended by deleting the evaluation planned after the further 9 months of treatment. Due to regulatory purposes, the study was conducted with an assumption of non-inferiority in place of the original hypothesis of superiority (with the corresponding change in the statistical part). Furthermore, with this amendment the number of sites was increased by adding new sites in Russia.
    24 Sep 2012
    Substantial amendment No. 2 (country specific: Latvia): After the amendment No. 1 and with the deletion of the evaluations at 24 and 48 weeks, it was specifically requested, due to ethical reason, that the study would have guaranteed to the patients a treatment course for onychomycosis of 48 weeks, as recommended by international guidelines. Thus, once the patients completed the three months of treatment foreseen as primary endpoint by the original protocol and as secondary endpoints scheduled by Protocol amendment No. 1, they entered in a 9-month “active follow up phase”, provided with the needed drugs. Based on this amendment, the safety, efficacy and tolerability data, collected after 24 and 48 weeks of treatment in the Latvian centre have been presented in a separate analysis and described in this integrative report.
    01 Feb 2014
    Non-substantial amendment No. 3 (country specific: Latvia): This non-substantial amendment regarded the specification of the responsibility for the evaluation of the pictures inserted in the electronic case report form (eCRF), related the progression of the disease in the patients enrolled, and data used for the evaluation of the secondary study endpoints. Therefore, in order to guarantee the homogeneity of the evaluations and to improve the scientific value of the trial, an external parallel evaluation in blind, performed by an independent Medical Expert (Central Blinded Assessor) was scheduled. Only data from the Latvian centre derived this central evaluation were used for the final statistical analysis. Deviations in the non-substantial amendment No. 3 occurred in the final analysis. In fact, the Blinded Assessor evaluated the progression of the disease of all patients enrolled, but produced a report related to Visits 6 and 7 (24 and 48 weeks, respectively) only, due to the fact that a responsiveness/cure was unlikely reached within 12 weeks of treatment only as per disease conditions.
    14 May 2014
    Non-substantial amendment No. 4 (country specific: Latvia): This non-substantial amendment regarded the decision of not performing of the exploratory objective of the study (evaluation of nail concentration of ciclopirox and amorolfine) initially planned in the study protocol, by collecting patients’ nail samples. The Sponsor decided not to perform this examination because in a very recent paper published by Monti et al (18 - the data, not available when the protocol was written, have been reported). Consequently, the examination has been deleted for futility. On the other hand, with this amendment and according to the exclusion criteria reported in the study protocol, the Sponsor intended to detect the use of systemic terbinafine (the most common systemic drug for the treatment of onychomycosis) on the affected nail, at the end of treatment, analysing the samples initially collected for the PK analysis. Those patients with a detectable terbinafine concentration above 0.9 μg/mL, which corresponds to the nail terbinafine concentration after a 16 and 30 days oral terbinafine multiple-dose administration, according to the paper of Kovarik et al (17), were excluded from the PP population at 12 and 48 weeks during the statistical analysis of the results of the study.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27171791
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