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    Clinical Trial Results:
    A first–in-human study to evaluate safety and tolerability of repeated topical administrations of BPR277 ointment in healthy volunteers, and safety, tolerability, and preliminary efficacy of multiple topical administrations of BPR277 in patients with atopic dermatitis and Netherton syndrome

    Summary
    EudraCT number
    		 2011-000917-38
    Trial protocol
    		 DE   NL  
    Global end of trial date
    13 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    08 Aug 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CBPR277X2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01428297
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    There were three parts to this study: Part 1 : A partially blinded intra-individual, vehicle controlled cohort to demonstrate tolerability (systemic and local) of repeated twice daily applications of BPR277 ointment in healthy volunteers Part 2 : A double blind, inter-individual vehicle controlled cohort to evaluate tolerability and whether BPR277 1% ointment b.i.d. could maintain a treatment effect induced by topical corticosteroids in Atopic Dermatitis (AD) patients. Part 3 : A double blind and intra-individual controlled cohorts to assess tolerability and the potential of BPR277 1% ointment (applied b.i.d in Part 3 Cohorts A & AA or q.d in Part 3 Cohort AB) to improve the clinical severity of lesional skin (TLSS-NS) in Netherton Syndrome (ND) patients
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. It is recommended, in particular in Parts 2 and 3A, AA & AB, to use a low potent TCS, such as hydrocortisone 2.5%, for the rest of the body if emollients are not sufficient, but if medically needed the investigator may need to use higher strengths or topical calcineurin inhibitors (pimecrolimus, tacrolimus). If the flare is restricted to areas outside the treatment area, do not apply the rescue medication to the selected treatment area and at least 10cm around.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 37
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 31
    Worldwide total number of subjects
    79
    EEA total number of subjects
    42
    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)
    79
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Study consists of three parts. Healthy volunteers will be recruited for Part 1, subjects with Atopic Dermatitis for Part 2 and subjects with Netherton Syndrome (NS) for Part 3.

    Pre-assignment
    Screening details
    		 Each of the three Parts of the study had it's own unique screening period designed to screen for the appropriate subjects for the treatment period (Part 1 - Healthy Volunteers (HV), Part 2 - Atopic Dermatitis (AD) and Part 3 - Netherton Syndrome (NS).

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HV Part 1 Cohort 1A
    Arm description
    		 For Cohort A an area of 100 cm2 (10x10 cm) on the volar side of one forearm, including the antecubital fossa, will be treated with the 1% BPR277 ointment and two separate areas of 25 cm2 (5x5 cm) on the lower back will be treated with either 1% BPR277 ointment or vehicle ointment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BPR277
    Investigational medicinal product code
    BPR277
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects in Part 1 Cohort 1A were randomized to one of the following sequences: • Sequence 1: 1% BPR277 on 100cm2 forearm + 1% BPR277 on 25cm2 lower back right side + Vehicle on 25cm2 lower back left side • Sequence 2: 1% BPR277 on 100cm2 forearm + Vehicle on 25cm2 lower back right side + 1% BPR277 on 25cm2 lower back left side

    Arm title
    		 HV Part 1 Cohort 1B
    Arm description
    		 For Cohort B an area of 1250 cm2 of one arm was treated with the 1% BPR277 ointment and two separate areas of 25 cm2 on the lower back were treated with 0.2% BPR277 ointment or vehicle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BPR277
    Investigational medicinal product code
    BPR277
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects in Cohort 1B were randomized to one of the following sequences: • Sequence 1: 1% BPR277 on 1250cm2 arm + 0.2% BPR277 on 25cm2 lower back right side + Vehicle on 25cm2 lower back left side • Sequence 2: 1% BPR277 on 1250cm2 arm + Vehicle on 25cm2 lower back right side + 0.2% BPR277 on 25cm2 lower back left side

    Arm title
    		 Atopic Dermatitis Part 2 1% BPR277
    Arm description
    		 Patients applied 0.5 g b.i.d. of either 1% BPR277 ointment or its vehicle (corresponding to 10 mg/d of BPR277 for the active group) over 4 weeks to a 250 cm2 selected treatment area.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BPR277
    Investigational medicinal product code
    BPR277
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    A qualifying 250 cm2 area of skin containing at least 50% AD affected skin (i.e., at least 125 cm2 affected with atopic dermatitis lesions at screening) was chosen. The study drug was applied twice daily (morning and evening) for 4 weeks.

    Arm title
    		 Atopic Dermatitis Part 2 Vehicle
    Arm description
    		 Patients applied 0.5 g b.i.d. of either 1% BPR277 ointment or its vehicle (corresponding to 10 mg/d of BPR277 for the active group) over 4 weeks to a 250 cm2 selected treatment area.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BPR277
    Investigational medicinal product code
    BPR277
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    A qualifying 250 cm2 area of skin containing at least 50% AD affected skin (i.e., at least 125 cm2 affected with atopic dermatitis lesions at screening) was chosen. The study drug was applied twice daily (morning and evening) for 4 weeks.

    Arm title
    		 Netherton Syndrome Cohort 3A BID 250 cm2
    Arm description
    		 BID 250 cm2 In Cohort 3A, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 b.i.d on Area 1 + Vehicle on Area 2 • Sequence 2: Vehicle b.i.d on Area 1+ 1% BPR277 on Area 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    BPR277
    Investigational medicinal product code
    BPR277
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    The patient was instructed on how to apply the study drug (1% BPR277 ointment or vehicle as per randomization). Patient was supervised for the first application to the selected treatment areas on Day 1 to ensure patient did not mix up treatment applications. Patients were dispensed three tubes on Day 1 and 15, and two tubes on Day 8 and 22. The study drug was applied twice daily (morning and evening) for 4 weeks.

    Arm title
    		 Netherton Syndrome Cohort 3AA BID 500 cm2
    Arm description
    		 BID 500 cm2 In Cohort 3AA, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 b.i.d on Area 1 + Vehicle b.i.d. on Area 2 • Sequence 2: Vehicle b.i.d. on Area 1+ 1% BPR277 b.i.d. on Area 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    BPR277
    Investigational medicinal product code
    BPR277
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    The patient was instructed on how to apply the study drug (1% BPR277 ointment or vehicle as per randomization). Patient was supervised for the first application to the selected treatment areas on Day 1 to ensure patient did not mix up treatment applications. Patients were dispensed three tubes on Day 1 and 15, and two tubes on Day 8 and 22. The study drug was applied twice daily (morning and evening) for 4 weeks.

    Arm title
    		 Netherton Syndrome Cohort 3AB QD 500 cm2
    Arm description
    		 QD 500 cm2 In Cohort 3AB, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 q.d. on Area 1 + Vehicle q.d. on Area 2 • Sequence 2: Vehicle q.d. on Area 1 + 1% BPR277 q.d. on Area 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    BPR277
    Investigational medicinal product code
    BPR277
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    In Cohort 3AB patients applied 1% BPR277 ointment once a day (q.d.) over 4 weeks (corresponding to 10 mg/d of BPR277 applied to a surface of approximately 500 cm2) and vehicle similarly.

    Number of subjects in period 1
    		HV Part 1 Cohort 1A HV Part 1 Cohort 1B Atopic Dermatitis Part 2 1% BPR277 Atopic Dermatitis Part 2 Vehicle Netherton Syndrome Cohort 3A BID 250 cm2 Netherton Syndrome Cohort 3AA BID 500 cm2 Netherton Syndrome Cohort 3AB QD 500 cm2
    Started
    6
    6
    25
    24
    7
    5
    6
    Completed
    6
    6
    25
    23
    7
    5
    5
    Not completed
    0
    0
    0
    1
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    HV Part 1 Cohort 1A
    Reporting group description
    		 For Cohort A an area of 100 cm2 (10x10 cm) on the volar side of one forearm, including the antecubital fossa, will be treated with the 1% BPR277 ointment and two separate areas of 25 cm2 (5x5 cm) on the lower back will be treated with either 1% BPR277 ointment or vehicle ointment.

    Reporting group title
    HV Part 1 Cohort 1B
    Reporting group description
    		 For Cohort B an area of 1250 cm2 of one arm was treated with the 1% BPR277 ointment and two separate areas of 25 cm2 on the lower back were treated with 0.2% BPR277 ointment or vehicle.

    Reporting group title
    Atopic Dermatitis Part 2 1% BPR277
    Reporting group description
    		 Patients applied 0.5 g b.i.d. of either 1% BPR277 ointment or its vehicle (corresponding to 10 mg/d of BPR277 for the active group) over 4 weeks to a 250 cm2 selected treatment area.

    Reporting group title
    Atopic Dermatitis Part 2 Vehicle
    Reporting group description
    		 Patients applied 0.5 g b.i.d. of either 1% BPR277 ointment or its vehicle (corresponding to 10 mg/d of BPR277 for the active group) over 4 weeks to a 250 cm2 selected treatment area.

    Reporting group title
    Netherton Syndrome Cohort 3A BID 250 cm2
    Reporting group description
    		 BID 250 cm2 In Cohort 3A, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 b.i.d on Area 1 + Vehicle on Area 2 • Sequence 2: Vehicle b.i.d on Area 1+ 1% BPR277 on Area 2

    Reporting group title
    Netherton Syndrome Cohort 3AA BID 500 cm2
    Reporting group description
    		 BID 500 cm2 In Cohort 3AA, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 b.i.d on Area 1 + Vehicle b.i.d. on Area 2 • Sequence 2: Vehicle b.i.d. on Area 1+ 1% BPR277 b.i.d. on Area 2

    Reporting group title
    Netherton Syndrome Cohort 3AB QD 500 cm2
    Reporting group description
    		 QD 500 cm2 In Cohort 3AB, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 q.d. on Area 1 + Vehicle q.d. on Area 2 • Sequence 2: Vehicle q.d. on Area 1 + 1% BPR277 q.d. on Area 2

    Reporting group values
    		 HV Part 1 Cohort 1A HV Part 1 Cohort 1B Atopic Dermatitis Part 2 1% BPR277 Atopic Dermatitis Part 2 Vehicle Netherton Syndrome Cohort 3A BID 250 cm2 Netherton Syndrome Cohort 3AA BID 500 cm2 Netherton Syndrome Cohort 3AB QD 500 cm2 Total
    Number of subjects
    		 6 6 25 24 7 5 6 79
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 6 25 24 7 5 6 79
    Gender categorical
    Units: Subjects
        Female
    		 3 3 12 13 3 1 3 38
        Male
    		 3 3 13 11 4 4 3 41

    End points

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    End points reporting groups
    Reporting group title
    HV Part 1 Cohort 1A
    Reporting group description
    		 For Cohort A an area of 100 cm2 (10x10 cm) on the volar side of one forearm, including the antecubital fossa, will be treated with the 1% BPR277 ointment and two separate areas of 25 cm2 (5x5 cm) on the lower back will be treated with either 1% BPR277 ointment or vehicle ointment.

    Reporting group title
    HV Part 1 Cohort 1B
    Reporting group description
    		 For Cohort B an area of 1250 cm2 of one arm was treated with the 1% BPR277 ointment and two separate areas of 25 cm2 on the lower back were treated with 0.2% BPR277 ointment or vehicle.

    Reporting group title
    Atopic Dermatitis Part 2 1% BPR277
    Reporting group description
    		 Patients applied 0.5 g b.i.d. of either 1% BPR277 ointment or its vehicle (corresponding to 10 mg/d of BPR277 for the active group) over 4 weeks to a 250 cm2 selected treatment area.

    Reporting group title
    Atopic Dermatitis Part 2 Vehicle
    Reporting group description
    		 Patients applied 0.5 g b.i.d. of either 1% BPR277 ointment or its vehicle (corresponding to 10 mg/d of BPR277 for the active group) over 4 weeks to a 250 cm2 selected treatment area.

    Reporting group title
    Netherton Syndrome Cohort 3A BID 250 cm2
    Reporting group description
    		 BID 250 cm2 In Cohort 3A, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 b.i.d on Area 1 + Vehicle on Area 2 • Sequence 2: Vehicle b.i.d on Area 1+ 1% BPR277 on Area 2

    Reporting group title
    Netherton Syndrome Cohort 3AA BID 500 cm2
    Reporting group description
    		 BID 500 cm2 In Cohort 3AA, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 b.i.d on Area 1 + Vehicle b.i.d. on Area 2 • Sequence 2: Vehicle b.i.d. on Area 1+ 1% BPR277 b.i.d. on Area 2

    Reporting group title
    Netherton Syndrome Cohort 3AB QD 500 cm2
    Reporting group description
    		 QD 500 cm2 In Cohort 3AB, patients were randomly allocated to one of the two following sequences to enable randomization of the location of treatment: • Sequence 1: 1% BPR277 q.d. on Area 1 + Vehicle q.d. on Area 2 • Sequence 2: Vehicle q.d. on Area 1 + 1% BPR277 q.d. on Area 2

    Subject analysis set title
    AD PD Analysis Set - BPR277
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects with any evaluable PD parameter data and without protocol deviations impacting the PD analysis were included in the PD analysis sets. In part 2 however there was a “2nd PD population” excluding one patient who received the incorrect treatment.

    Subject analysis set title
    AD PD Analysis Set - Vehicle
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects with any evaluable PD parameter data and without protocol deviations impacting the PD analysis were included in the PD analysis sets. In part 2 however there was a “2nd PD population” excluding one patient who received the incorrect treatment.

    Subject analysis set title
    NS PD BPR277 b.i.d.
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Protocol deviations were reported for2 subjects in Cohort 3A which excluded them from the PD analysis.

    Subject analysis set title
    NS PD Vehicle b.i.d.
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Protocol deviations were reported for 2 subjects in Cohort 3A which excluded them from the PD analysis.

    Subject analysis set title
    NS PD BPR277 q.d.
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cohort AB for q.d. dosing with 1 patient not included because lost to follow up.

    Subject analysis set title
    NS PD Vehicle q.d.
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cohort AB for q.d. dosing with 1 patient not included because lost to follow up.

    Subject analysis set title
    NS Total BPR277
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received BPR277 from all 3 cohorts minus 2 patients with protocol deviations and 1 lost to follow-up.

    Subject analysis set title
    NS Total Vehicle
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received Vehicle from all 3 cohorts minus 2 patients with protocol deviations and 1 lost to follow-up.

    Primary: Demonstrate tolerability (systemic and local) of repeated twice daily topical applications of BPR277 in adult subjects, and in patients with AD and NS (all parts).

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    End point title
    		 Demonstrate tolerability (systemic and local) of repeated twice daily topical applications of BPR277 in adult subjects, and in patients with AD and NS (all parts). [1] [2]
    End point description
    Refer to safety section.
    End point type
    Primary
    End point timeframe
    Adverse events were collected from first dose of study medication until resolution. Serious Adverse Events were collected from signing of Informed Consent through 30 days post drug.
    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: Only summary statistics.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms of comparable dose were included as per planned analysis.
    End point values
    		 HV Part 1 Cohort 1A Atopic Dermatitis Part 2 1% BPR277 Atopic Dermatitis Part 2 Vehicle Netherton Syndrome Cohort 3A BID 250 cm2 Netherton Syndrome Cohort 3AA BID 500 cm2 Netherton Syndrome Cohort 3AB QD 500 cm2
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    Units: Incidence of Adverse Events
    Notes
    [3] - Refer to Safety Section.
    [4] - Refer to Safety Section
    [5] - Refer to Safety Section.
    [6] - Refer to Safety Section.
    [7] - Refer to Safety Section.
    [8] - Refer to Safety Section
    No statistical analyses for this end point

    Primary: Part 2, evaluate whether BPR277 ointment b.i.d. maintained a treatment effect, induced by topical corticosteroids, by assessing that the TLSS increase was at most half of that of its vehicle in AD patients.

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    End point title
    		 Part 2, evaluate whether BPR277 ointment b.i.d. maintained a treatment effect, induced by topical corticosteroids, by assessing that the TLSS increase was at most half of that of its vehicle in AD patients.
    End point description
    The Total Lesional Sign Score (TLSS) was assessed at each week for the treatment areas. For each patient the slope of the score versus time curve was calculated in order to estimate the rate of increase of score with time, i.e. the rate of relapse.
    End point type
    Primary
    End point timeframe
    4 weeks
    End point values
    		 AD PD Analysis Set - BPR277 AD PD Analysis Set - Vehicle
    Number of subjects analysed
    23
    22
    Units: Rate of increase of TLSS
        arithmetic mean (standard error)
    0.13 ( 0.029 )
    0.08 ( 0.029 )
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    A positive sign of efficacy was considered to be a difference of at least 0.5 in the slope of the score versus time curve between BPR277 and vehicle with at least 70% level of proof. Additionally there should be evidence that there was some difference between BPR277 and vehicle with at least 90% level of proof.
    Comparison groups
    AD PD Analysis Set - BPR277 v AD PD Analysis Set - Vehicle
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 > 0.1 [10]
    Method
    		 Bayesian credibility interval
    Parameter type
    		 Slope
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 0.15
    Notes
    [9] - The probability is calculated from the simulated posterior distributions of θ (BPR277) and θ (Vehicle) which are constructed from Bayesian analysis with a non-informative Jeffery’s prior distribution. 95% BCI = 95% Bayesian credibility interval
    [10] - Vehicle p = 0.1% BPR277 p = 7.8% The probability is calculated from the simulated posterior distributions of θ (1% BPR277) and θ (Vehicle) which are constructed from Bayesian analysis with a non-informative Jeffery’s prior distribution.

    Primary: Netherton Syndrome Summary of clinical response (2 points)

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    End point title
    		 Netherton Syndrome Summary of clinical response (2 points) [11]
    End point description
    Lesions treated with BPR277 and with vehicle were evaluated separately. A lesion was considered as having a clinical response if the reduction in TLSS-NS score at the end of treatment compared to baseline was ≥ 2 points. Posterior probability > 0.5; 95% BCI = 95% Bayesian credibility interval.
    End point type
    Primary
    End point timeframe
    At week 4.
    Notes
    [11] - 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: The summary of the treatments is presented. Posterior probability > 0.5; 95% BCI = 95% Bayesian credibility interval was used.
    End point values
    		 NS PD BPR277 b.i.d. NS PD Vehicle b.i.d. NS PD BPR277 q.d. NS PD Vehicle q.d. NS Total BPR277 NS Total Vehicle
    Number of subjects analysed
    10
    10
    5
    5
    15
    15
    Units: Responders
    number (not applicable)
        Responders
    6
    0
    1
    1
    7
    1
        Responders (percent)
    60
    0
    20
    20
    47
    7
        Pr (p≥0.5|data)
    0.739
    0.001
    0.08
    0.08
    0.398
    0.001
        95% BCI Lower
    0.302
    0
    0.016
    0.016
    0.236
    0.005
        95% BCI Upper
    0.852
    0.182
    0.622
    0.622
    0.708
    0.26
    No statistical analyses for this end point

    Secondary: Summary of BPR277 exposure data AUC0-24h,ss (h*ng/mL)

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    End point title
    		 Summary of BPR277 exposure data AUC0-24h,ss (h*ng/mL) [12]
    End point description
    • Evaluate systemic steady state pharmacokinetics in human after topical administration of BPR277 ointment. • Determine BPR277 concentrations in the skin and the urinary excretion of BPR277 after repeated topical administration of BPR277 ointment in adult HV subjects and patients with AD and NS (for NS only in Part 3A). • Assess the ability of repeated topical applications of BPR277 to restore the skin barrier function in AD and NS patients as demonstrated by the change in Transepidermal Water Reported values of <LLOQ as 0. Reported ~ 1 as 1.
    End point type
    Secondary
    End point timeframe
    Part 1 • Days 1, 3, 5, 8, and 11 predose, day 22 • Day 14: pre-dose and 1, 3, 7, and 12 h after the morning dose Part 2 and Cohort 3A • Days 1, 8, 15 and 22 predose,day 43 • Day 29: pre-dose and 1, 3, 7, and 12 h after the morning dose
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms of comparable dose were included (250 cm2). Vehicle and 500 cm^2 were excluded. Secondary endpoint.
    End point values
    		 HV Part 1 Cohort 1A HV Part 1 Cohort 1B AD PD Analysis Set - BPR277 NS PD BPR277 b.i.d.
    Number of subjects analysed
    6
    6
    23
    10
    Units: h*ng/mL
    number (not applicable)
        AUC0-24h,ss (h*ng/mL)
    0
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Summary of BPR277 exposure data - Median skin concentration (ng/g)

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    End point title
    		 Summary of BPR277 exposure data - Median skin concentration (ng/g) [13]
    End point description
    • Evaluate systemic steady state pharmacokinetics in human after topical administration of BPR277 ointment. • Determine BPR277 concentrations in the skin and the urinary excretion of BPR277 after repeated topical administration of BPR277 ointment in adult HV subjects and patients with AD and NS (for NS only in Part 3A). • Assess the ability of repeated topical applications of BPR277 to restore the skin barrier function in AD and NS patients as demonstrated by the change in Transepidermal Water
    End point type
    Secondary
    End point timeframe
    Part 1 • Days 1, 3, 5, 8, and 11 predose, day 22 • Day 14: pre-dose and 1, 3, 7, and 12 h after the morning dose Part 2 and Cohort 3A • Days 1, 8, 15 and 22 predose,day 43 • Day 29: pre-dose and 1, 3, 7, and 12 h after the morning dose
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Secondary endpoint.
    End point values
    		 HV Part 1 Cohort 1A HV Part 1 Cohort 1B AD PD Analysis Set - BPR277 NS PD BPR277 b.i.d.
    Number of subjects analysed
    6
    6
    23
    10
    Units: ng/g
    number (not applicable)
        Median skin concentration
    1050
    1070
    4870
    1810
    No statistical analyses for this end point

    Secondary: Summary of BPR277 exposure data - Median fraction of dose in urine (%)

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    End point title
    		 Summary of BPR277 exposure data - Median fraction of dose in urine (%) [14]
    End point description
    •Evaluate systemic steady state pharmacokinetics in human after topical administration of BPR277 ointment. •Determine BPR277 concentrations in the skin and the urinary excretion of BPR277 after repeated topical administration of BPR277 ointment in adult HV subjects and patients with AD and NS (for NS only in Part 3A). •Assess the ability of repeated topical applications of BPR277 to restore the skin barrier function in AD and NS patients as demonstrated by the change in Transepidermal Water Values •<LLOQ were reported as O and analyzed as 0 for Median fraction of dose in urine.
    End point type
    Secondary
    End point timeframe
    Part 1 • Days 1, 3, 5, 8, and 11 predose, day 22 • Day 14: pre-dose and 1, 3, 7, and 12 h after the morning dose. Part 2 and Cohort 3A • Days 1, 8, 15 and 22 predose,day 43 • Day 29: pre-dose and 1, 3, 7, and 12 h after the morning dose
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms of comparable dose were included as per planned analysis.
    End point values
    		 HV Part 1 Cohort 1A HV Part 1 Cohort 1B AD PD Analysis Set - BPR277 NS PD BPR277 b.i.d.
    Number of subjects analysed
    6
    6
    23
    10
    Units: Percent
    median (full range (min-max))
        Median fraction of dose in urine (%)
    0 (0 to 0.015)
    0 (0 to 0.00199)
    0.011 (0 to 0.169)
    0.001 (0 to 0.042)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Part 1 - Cohort A
    Reporting group description
    		 Part 1 - Cohort A

    Reporting group title
    Part 2 - 1% BPR277
    Reporting group description
    		 Part 2 - 1% BPR277

    Reporting group title
    Part 3 - Cohort AB
    Reporting group description
    		 Part 3 - Cohort AB

    Reporting group title
    Part 3 - Cohort A
    Reporting group description
    		 Part 3 - Cohort A

    Reporting group title
    Part 3 - Cohort AA
    Reporting group description
    		 Part 3 - Cohort AA

    Reporting group title
    Part 2 - Vehicle
    Reporting group description
    		 Part 2 - Vehicle

    Serious adverse events
    		 Part 1 - Cohort A Part 2 - 1% BPR277 Part 3 - Cohort AB Part 3 - Cohort A Part 3 - Cohort AA Part 2 - Vehicle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 - Cohort A Part 2 - 1% BPR277 Part 3 - Cohort AB Part 3 - Cohort A Part 3 - Cohort AA Part 2 - Vehicle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    9 / 25 (36.00%)
    4 / 6 (66.67%)
    6 / 7 (85.71%)
    3 / 5 (60.00%)
    7 / 24 (29.17%)
    Investigations
    Blood uric acid increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Procedural site reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Sports injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 25 (8.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 24 (8.33%)
         occurrences all number
    1
    3
    1
    0
    2
    2
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 25 (12.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    4
    0
    0
    0
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 25 (4.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Infections and infestations
    Incision site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 25 (24.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    7
    0
    2
    0
    3
    Otitis media
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 25 (4.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 25 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jan 2012
    For Part 2 conducted in AD patients: • The location options for the treatment area were expanded. Additional particular body locations were permissible to ensure a broad AD population was eligible for the study. • The TEWL assessment was no longer required at the antecubital fossa location, due to the expansion of treatment area location options. The TEWL was now required within the treatment area and outside the treatment area. • An additional 2 day extension was allowed for the TCS pre-treatment period to permit greater flexibility in scheduling patient visits. • A global clinical assessment (IGA-WB) on the whole body (minus the study treatment area) was included to follow the evolution of the overall disease outside the treated area. For Parts 2 and 3 of the study, conducted in patients: • The unblinding procedure during exploratory interim analyses was clarified, including a list of team members who might have been unblinded at these times. • The conditions (i.e. temperature, humidity, and standard deviation) of the TEWL assessment were clarified / updated. • The time window for the skin tape stripping procedure and PK blood sampling was clarified.
    25 Jul 2012
    • Addition of two new cohorts (B & C) to Part 3 of the study in NS patients in order to gather additional safety and efficacy data when BPR277 ointment was applied over larger areas of the skin surface (approximately 1500 cm2) at different concentrations (vehicle, 0.2% and 1%) and treatment regimens (b.i.d. and q.d.). • Biomarker data would continue to be gathered in these additional cohorts, including tape strips and skin biopsies to understand more about BPR277’s mechanism of action. A pharmacogenetic blood sample was also proposed for all patients in Part 3, which was optional in Cohort A. • As NS is a rare disease and the topical application of BPR277 ointment over 4 weeks was considered well tolerated, it was proposed that NS patients who participated in Part 3A be allowed to be screened for entry into either of the newly added cohorts provided that >6 months had elapsed since their last application of BPR277.
    25 Feb 2013
    • The study design was adjusted to take an approach that confirmed previous results from the first cohort in Netherton syndrome and included an additional dose-regimen (b.i.d and q.d) aspect. This modified study design meant that the 0.2% BPR277 formulation would not be investigated, as originally planned in amendment 3. Instead, the 1% BPR277 formulation (versus vehicle) was studied when applied on up to 500cm2 of lesional skin using b.i.d and q.d dosing regimens. • Additional biomarkers (such as the RNA-based assessment in skin biopsy) and by using novel, non-invasive techniques including epidermal barrier and skin lipid analysis were introduced to further explore the mechanism of action of this kallikrein 7 inhibitor.
    20 Jun 2013
    Testing for the presence of the SPINK5 gene mutation and/or LEKTI deficiency in the skin was incorporated, in order to confirm the diagnosis of Netherton syndrome.

    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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