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    Clinical Trial Results:
    A randomized, double-blinded, regimen controlled, phase II, multicenter study to assess the efficacy and safety of two different vismodegib regimens in patients with multiple basal cell carcinomas

    Summary
    EudraCT number
    		 2012-003305-10
    Trial protocol
    		 AT   DE   NL   IT   ES   FR  
    Global end of trial date
    31 Aug 2016

    Results information
    Results version number
    		 v3(current)
    This version publication date
    15 Sep 2017
    First version publication date
    13 Jul 2016
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MO28295
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01815840
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    31 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This randomized, double-blind, regimen-controlled, phase II, multicenter study assessed the efficacy and safety of two different vismodegib regimens in subjects with multiple basal cell carcinoma. Subjects received vismodegib 150 mg orally once daily either in an intermittent schedule of 12 weeks vismodegib followed by 8 weeks placebo (Arm A) or as 24 weeks induction followed by an intermittent schedule of 8 weeks placebo followed by 8 weeks vismodegib (Arm B). Anticipated time on study treatment was 72 weeks.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Austria: 12
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    229
    EEA total number of subjects
    149
    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)
    127
    From 65 to 84 years
    94
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 229 subjects were enrolled in 10 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vismodegib Intermittent Schedule
    Arm description
    		 Vismodegib intermittent schedule of 12 weeks vismodegib followed by 8 weeks placebo, repeated 3 times with a final course of vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Erivedge®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vismodegib 150 mg hard gelatin capsule orally once daily

    Investigational medicinal product name
    Vismodegib Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vismodegib placebo orally once daily

    Arm title
    		 Vismodegib Induction Followed by Intermittent Schedule
    Arm description
    		 Vismodegib beginning with 24 weeks induction followed by intermittent schedule 8 weeks placebo, 8 weeks vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Erivedge®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vismodegib 150 mg hard gelatin capsule orally once daily

    Investigational medicinal product name
    Vismodegib Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vismodegib placebo orally once daily

    Number of subjects in period 1
    		Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Started
    116
    113
    Completed
    57
    50
    Not completed
    59
    63
         Withdrew Consent
    31
    30
         Disease progression
    3
    2
         Sponsor Termination Treatment
    1
    -
         Adverse Event
    10
    16
         Other pre-specified
    1
    -
         Death
    2
    2
         Refused Treatment
    5
    1
         Administrative/Other
    1
    3
         Investigators Decision
    2
    3
         Lost to follow-up
    3
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vismodegib Intermittent Schedule
    Reporting group description
    		 Vismodegib intermittent schedule of 12 weeks vismodegib followed by 8 weeks placebo, repeated 3 times with a final course of vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up

    Reporting group title
    Vismodegib Induction Followed by Intermittent Schedule
    Reporting group description
    		 Vismodegib beginning with 24 weeks induction followed by intermittent schedule 8 weeks placebo, 8 weeks vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up

    Reporting group values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule Total
    Number of subjects
    		 116 113 229
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.1 ( 13.94 ) 59.9 ( 15.35 ) -
    Gender categorical
    Units: Subjects
        Female
    		 35 25 60
        Male
    		 81 88 169

    End points

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    End points reporting groups
    Reporting group title
    Vismodegib Intermittent Schedule
    Reporting group description
    		 Vismodegib intermittent schedule of 12 weeks vismodegib followed by 8 weeks placebo, repeated 3 times with a final course of vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up

    Reporting group title
    Vismodegib Induction Followed by Intermittent Schedule
    Reporting group description
    		 Vismodegib beginning with 24 weeks induction followed by intermittent schedule 8 weeks placebo, 8 weeks vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up

    Primary: Mean Percent Change From Baseline in the Number of Clinically Evident Basal Cell Carcinomas at Week 73 (After 72 Weeks of Treatment)

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    End point title
    		 Mean Percent Change From Baseline in the Number of Clinically Evident Basal Cell Carcinomas at Week 73 (After 72 Weeks of Treatment)
    End point description
    The total number of clinically evident basal cell carcinomas = the total number of target and/or non-target lesions present in individual subjects. Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis. The last observation carried forward method was used.
    End point type
    Primary
    End point timeframe
    Baseline; Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    114
    113
    Units: percent change
        arithmetic mean (standard deviation)
    62.9 ( 52.01 )
    54.9 ( 54.85 )
    Statistical analysis title
    		 Difference in mean relative reduction
    Statistical analysis description
    The mean difference in the mean relative reduction between treatment arms, along with the corresponding 95% confidence interval, was estimated by fitting an ANCOVA model with treatment as main effect and the following covariates: number of basal cell carcinomas at baseline, geographical region, immunosuppression status, confirmed basal cell carcinoma nevus syndrome. Asymptotic confidence intervals are presented for the difference between treatment arms.
    Comparison groups
    Vismodegib Intermittent Schedule v Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.2
         upper limit
    		 5.7

    Secondary: Percentage of Subjects Who Discontinued Study Treatment Due to Tolerability Issues

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    End point title
    		 Percentage of Subjects Who Discontinued Study Treatment Due to Tolerability Issues
    End point description
    The percentage of subjects who discontinued study treatment (due either to adverse event, refusal of treatment, or withdrawal of consent) was summarized by treatment group. Intent-to-Treat Analysis Population, defined as all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    116
    113
    Units: percentage of subjects
    number (confidence interval 95%)
        Overall
    37.1 (28.3 to 46.5)
    41.6 (32.4 to 51.2)
        Adverse Events
    20.7 (13.7 to 29.2)
    27.4 (19.5 to 36.6)
        Refused Treatment
    6 (2.5 to 12)
    2.7 (0.6 to 7.6)
        Withdrew Consent
    10.3 (5.5 to 17.4)
    11.5 (6.3 to 18.9)
    No statistical analyses for this end point

    Secondary: Mean Percent Change From Baseline in Total Size of Three Target Basal Cell Carcinoma Lesions in Individual Subjects at Week 73

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    End point title
    		 Mean Percent Change From Baseline in Total Size of Three Target Basal Cell Carcinoma Lesions in Individual Subjects at Week 73
    End point description
    The three target basal cell carcinoma lesions = the three largest visible lesions, at least 5 mm in the longest diameter, in individual subjects. Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    94
    85
    Units: percent change
        arithmetic mean (standard deviation)
    82.9 ( 27.01 )
    68 ( 53.02 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With at Least 50% Reduction in the Number of Basal Cell Carcinomas at Week 73

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    End point title
    		 Percentage of Subjects With at Least 50% Reduction in the Number of Basal Cell Carcinomas at Week 73
    End point description
    Intent-to-Treat Analysis Population, defined as all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    116
    113
    Units: percentage of subjects
        number (not applicable)
    65.5
    50.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With New Basal Cell Carcinomas at Week 73

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    End point title
    		 Percentage of Subjects With New Basal Cell Carcinomas at Week 73
    End point description
    Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    94
    86
    Units: percentage of subjects
    number (not applicable)
        No new lesions
    76.6
    74.4
        1 new lesion
    10.6
    11.6
        2 new lesions
    5.3
    5.8
        3 new lesions
    5.3
    2.3
        >3 new lesions
    2.1
    5.8
    No statistical analyses for this end point

    Secondary: Percent Change in Total Number of Basal Cell Carcinomas Relative to Baseline at Week 85 (12 Weeks Following End of Treatment) (Recurrence Rate)

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    End point title
    		 Percent Change in Total Number of Basal Cell Carcinomas Relative to Baseline at Week 85 (12 Weeks Following End of Treatment) (Recurrence Rate)
    End point description
    Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 85
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    90
    77
    Units: percent change
        arithmetic mean (standard deviation)
    35.7 ( 50.25 )
    38.5 ( 55.22 )
    No statistical analyses for this end point

    Secondary: Percent Change in Total Number of Basal Cell Carcinomas Relative to Baseline at Week 97 (24 Weeks Following End of Treatment) (Recurrence Rate)

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    End point title
    		 Percent Change in Total Number of Basal Cell Carcinomas Relative to Baseline at Week 97 (24 Weeks Following End of Treatment) (Recurrence Rate)
    End point description
    Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 97
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    84
    72
    Units: percent change
        arithmetic mean (standard deviation)
    36 ( 49.48 )
    42.1 ( 57.83 )
    No statistical analyses for this end point

    Secondary: Percent Change in Total Number of Basal Cell Carcinomas Relative to Baseline at Week 125 (52 Weeks Following End of Treatment) (Recurrence Rate)

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    End point title
    		 Percent Change in Total Number of Basal Cell Carcinomas Relative to Baseline at Week 125 (52 Weeks Following End of Treatment) (Recurrence Rate)
    End point description
    Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 125
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    95
    82
    Units: percent change
        arithmetic mean (standard deviation)
    41.2 ( 45.23 )
    44 ( 42.87 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Experiencing Any Adverse Event

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    End point title
    		 Percentage of Subjects Experiencing Any Adverse Event
    End point description
    Safety Analysis Population: Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 125 weeks
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    114
    113
    Units: percentage of subjects
        number (not applicable)
    99.1
    97.3
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in the Skindex-16 Symptom Domain Score at Week 73

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    End point title
    		 Percent Change From Baseline in the Skindex-16 Symptom Domain Score at Week 73
    End point description
    The Skindex-16 is a patient-reported outcome health questionnaire. Subjects were asked about their symptoms, and their answers were combined into a composite Symptom Domain Score. Scores range from 0 ("never bothered") to 100 ("always bothered"). Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    87
    79
    Units: percent change
        arithmetic mean (standard deviation)
    -14.9 ( 25.75 )
    -12.6 ( 23.98 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in the Skindex-16 Emotion Domain Score at Week 73

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    End point title
    		 Percent Change From Baseline in the Skindex-16 Emotion Domain Score at Week 73
    End point description
    The Skindex-16 is a patient-reported outcome health questionnaire. Subjects were asked about their emotional state, and their answers were combined into a composite Emotion Domain Score. Scores range from 0 ("never bothered") to 100 ("always bothered"). Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    87
    79
    Units: percent change
        arithmetic mean (standard deviation)
    -27.4 ( 27.71 )
    -28.9 ( 28.16 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in the Skindex-16 Function Domain Score at Week 73

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    End point title
    		 Percent Change From Baseline in the Skindex-16 Function Domain Score at Week 73
    End point description
    The Skindex-16 is a patient-reported outcome health questionnaire. Subjects were asked about their ability to function, and answers were combined into a composite Function Domain Score. Scores range from 0 ("never bothered") to 100 ("always bothered"). Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) with available data were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 73
    End point values
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Number of subjects analysed
    87
    79
    Units: percent change
        arithmetic mean (standard deviation)
    -9.5 ( 20.59 )
    -10.3 ( 26.03 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 125 weeks
    Adverse event reporting additional description
    Safety Analysis Population: Subjects in the Intent-to-Treat Analysis Population (defined as all randomized subjects) who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Vismodegib Intermittent Schedule
    Reporting group description
    		 Vismodegib intermittent schedule of 12 weeks vismodegib followed by 8 weeks placebo, repeated 3 times with a final course of vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up

    Reporting group title
    Vismodegib Induction Followed by Intermittent Schedule
    Reporting group description
    		 Vismodegib beginning with 24 weeks induction followed by intermittent schedule 8 weeks placebo, 8 weeks vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up

    Serious adverse events
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 114 (21.05%)
    23 / 113 (20.35%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 114 (0.88%)
    2 / 113 (1.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spindle cell sarcoma
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seminoma
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Primary amyloidosis
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cerebral cyst
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 114 (0.88%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudolymphoma
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Xanthelasma
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 114 (2.63%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 113 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 113 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vismodegib Intermittent Schedule Vismodegib Induction Followed by Intermittent Schedule
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 114 (93.86%)
    108 / 113 (95.58%)
    Investigations
    Weight decreased
         subjects affected / exposed
    24 / 114 (21.05%)
    21 / 113 (18.58%)
         occurrences all number
    31
    23
    Blood creatine phosphokinase increased
         subjects affected / exposed
    11 / 114 (9.65%)
    15 / 113 (13.27%)
         occurrences all number
    14
    24
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 114 (6.14%)
    5 / 113 (4.42%)
         occurrences all number
    8
    5
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 114 (1.75%)
    6 / 113 (5.31%)
         occurrences all number
    6
    11
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    76 / 114 (66.67%)
    75 / 113 (66.37%)
         occurrences all number
    123
    111
    Ageusia
         subjects affected / exposed
    13 / 114 (11.40%)
    14 / 113 (12.39%)
         occurrences all number
    16
    18
    Headache
         subjects affected / exposed
    10 / 114 (8.77%)
    14 / 113 (12.39%)
         occurrences all number
    10
    14
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    24 / 114 (21.05%)
    26 / 113 (23.01%)
         occurrences all number
    30
    31
    Asthenia
         subjects affected / exposed
    15 / 114 (13.16%)
    21 / 113 (18.58%)
         occurrences all number
    29
    31
    Pyrexia
         subjects affected / exposed
    1 / 114 (0.88%)
    8 / 113 (7.08%)
         occurrences all number
    1
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 114 (17.54%)
    20 / 113 (17.70%)
         occurrences all number
    35
    24
    Nausea
         subjects affected / exposed
    23 / 114 (20.18%)
    14 / 113 (12.39%)
         occurrences all number
    32
    25
    Abdominal pain
         subjects affected / exposed
    8 / 114 (7.02%)
    12 / 113 (10.62%)
         occurrences all number
    10
    12
    Constipation
         subjects affected / exposed
    9 / 114 (7.89%)
    8 / 113 (7.08%)
         occurrences all number
    11
    10
    Abdominal pain upper
         subjects affected / exposed
    9 / 114 (7.89%)
    5 / 113 (4.42%)
         occurrences all number
    12
    6
    Vomiting
         subjects affected / exposed
    7 / 114 (6.14%)
    4 / 113 (3.54%)
         occurrences all number
    8
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 114 (5.26%)
    5 / 113 (4.42%)
         occurrences all number
    7
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    72 / 114 (63.16%)
    73 / 113 (64.60%)
         occurrences all number
    100
    93
    Pruritus
         subjects affected / exposed
    8 / 114 (7.02%)
    13 / 113 (11.50%)
         occurrences all number
    13
    14
    Actinic keratosis
         subjects affected / exposed
    10 / 114 (8.77%)
    8 / 113 (7.08%)
         occurrences all number
    13
    11
    Eczema
         subjects affected / exposed
    6 / 114 (5.26%)
    0 / 113 (0.00%)
         occurrences all number
    7
    0
    Rash
         subjects affected / exposed
    3 / 114 (2.63%)
    7 / 113 (6.19%)
         occurrences all number
    3
    7
    Seborrhoeic dermatitis
         subjects affected / exposed
    6 / 114 (5.26%)
    2 / 113 (1.77%)
         occurrences all number
    8
    2
    Psychiatric disorders
    Insomina
         subjects affected / exposed
    5 / 114 (4.39%)
    6 / 113 (5.31%)
         occurrences all number
    6
    6
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    83 / 114 (72.81%)
    94 / 113 (83.19%)
         occurrences all number
    184
    194
    Arthralgia
         subjects affected / exposed
    18 / 114 (15.79%)
    16 / 113 (14.16%)
         occurrences all number
    25
    25
    Myalgia
         subjects affected / exposed
    18 / 114 (15.79%)
    12 / 113 (10.62%)
         occurrences all number
    27
    18
    Back pain
         subjects affected / exposed
    7 / 114 (6.14%)
    7 / 113 (6.19%)
         occurrences all number
    8
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 114 (6.14%)
    12 / 113 (10.62%)
         occurrences all number
    10
    15
    Folliculitis
         subjects affected / exposed
    10 / 114 (8.77%)
    8 / 113 (7.08%)
         occurrences all number
    13
    10
    Bronchitis
         subjects affected / exposed
    5 / 114 (4.39%)
    8 / 113 (7.08%)
         occurrences all number
    5
    10
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 114 (6.14%)
    5 / 113 (4.42%)
         occurrences all number
    13
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 114 (18.42%)
    17 / 113 (15.04%)
         occurrences all number
    32
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2013
    Changes included: additional guidance on amenorrhea/irregular menses; additional laboratory testing to include creatine kinase to further investigate muscle spasm events; additional guidance on Vismodegib in seminal fluid to ensure male subjects did not donate sperm during treatment and for 2 months after treatment; updated eligibility criteria to exclude 1) subjects known or suspected to abuse alcohol and 2) with known rare hereditary disturbance of galactose metabolism; amended drug interaction language to reflect updated core documents regarding possible interactions with metabolize ethinyl estradiol contraceptive steroids; alteration to statistical analysis measure of precision.
    01 Feb 2016
    In accordance with the revised Investigator’s Brochure, the protocol and informed consent forms of all ongoing vismodegib studies recommending 7 months for pregnancy prevention (breast-feeding and blood donations) were amended to reflect new information on elimination of vismodegib from the body after treatment discontinuation. The population PK model for elimination was updated and finalized with additional PK data up to 12 months post-treatment obtained in Study MO25616 (STEVIE), as a result of this analysis the time period for females to avoid pregnancy, breast-feeding and for males and females blood donations was increased from 7 to 9 months after the last administration of vismodegib.

    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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