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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BBT120126032001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

13 Aug 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Aug 2018

Was the trial ended prematurely?

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

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 46

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

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 title

Part 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject

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.

Are arms mutually exclusive

Yes

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.

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.

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 title

Part 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

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.

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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Reporting group title

BB2603 Cutaneous Pump Spray (Part 1)

Reporting group description

Reporting group title

Lamisil Spray (Part 1)

Reporting group description

Reporting group title

BB2603 Vehicle Control Spray (Part 1)

Reporting group description

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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Reporting group title

BB2603 Cutaneous Pump Spray (Part 1)

Reporting group description

Reporting group title

Lamisil Spray (Part 1)

Reporting group description

Reporting group title

BB2603 Vehicle Control Spray (Part 1)

Reporting group description

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

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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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 name

MedDRA

Dictionary version

21.0

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
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
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
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
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
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
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
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
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

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Were there any global substantial amendments to the protocol? Yes

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.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Percentage of Subjects with TP Recurrence - Part 2

Secondary: Percentage of Subjects with TP Recurrence - Part 2

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

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

Secondary: Mean OSI Total Score - Part 2

Secondary: Mean OSI Total Score - Part 2

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

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

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

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

Secondary: Percentage of Subjects with OM Improvement - Part 2

Secondary: Percentage of Subjects with OM Improvement - Part 2

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

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

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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