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    Clinical Trial Results:
    An open-label, multi-center, expanded access study of RAD001 in patients with angiomyolipoma associated with tuberous sclerosis complex (TSC)

    Summary
    EudraCT number
    2012-005397-63
    Trial protocol
    ES  
    Global end of trial date
    29 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Jun 2020
    First version publication date
    14 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001MES12
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Farmacéutica, S.A
    Sponsor organisation address
    Gran Vía de les Corts Catalanes, 764, Barcelona, Spain, 08013
    Public contact
    Departamento Médico de Oncología, Novartis Farmacéutica, S.A, 00 34900353036, eecc.novartis@novartis.com
    Scientific contact
    Departamento Médico de Oncología, Novartis Farmacéutica, S.A, 00 34900353036, eecc.novartis@novartis.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
    29 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the dose-limiting safety of everolimus in subjects with angiomyolipoma associated with TSC.
    Protection of trial subjects
    This study was conducted in compliance with Good Clinical Practice (GCP), including the archiving of essential documents.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 May 2013
    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
    Spain: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled at 15 study centres in Spain.

    Pre-assignment
    Screening details
    Subjects enrolled in this study were diagnosed with angiomyolipoma (AML) associated with TSC.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Everolimus
    Arm description
    Everolimus was administered following an oral daily continuous regimen of two 5 milligram (mg) tablets (10 mg, total daily dose) once a day at the same time everyday, either always with food or without food.
    Arm type
    Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug was administered at a daily dose of two 5 mg tablets (10 mg, total daily dose) once a day.

    Number of subjects in period 1
    Everolimus
    Started
    19
    Completed
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    Everolimus was administered following an oral daily continuous regimen of two 5 milligram (mg) tablets (10 mg, total daily dose) once a day at the same time everyday, either always with food or without food.

    Reporting group values
    Everolimus Total
    Number of subjects
    19 19
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    19 19
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    38 (20 to 62) -
    Gender categorical
    Units: Subjects
        Female
    13 13
        Male
    6 6
    Race
    Units: Subjects
        Caucasian
    19 19

    End points

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    End points reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    Everolimus was administered following an oral daily continuous regimen of two 5 milligram (mg) tablets (10 mg, total daily dose) once a day at the same time everyday, either always with food or without food.

    Primary: Number of Subjects With Dose-limiting Safety of Everolimus

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    End point title
    Number of Subjects With Dose-limiting Safety of Everolimus [1]
    End point description
    Safety population included all subjects who received at least one dose of study drug and had at least one post-baseline safety assessment.
    End point type
    Primary
    End point timeframe
    Up to approximately 16 months
    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: No statistical analysis was planned for this primary outcome measure
    End point values
    Everolimus
    Number of subjects analysed
    19
    Units: subjects
        Dose reduction
    3
        Temporary interruption
    3
        Dose reduction and Temporary interruption
    2
    No statistical analyses for this end point

    Secondary: Response rate : Percentage of Subjects With Response of Angiomyolipoma to Everolimus

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    End point title
    Response rate : Percentage of Subjects With Response of Angiomyolipoma to Everolimus
    End point description
    Tumour response was assessed radiologically using magnetic resonance imaging (MRI) or computerised axial tomography (CT) scans. Tumour evaluations were recommended to be performed for all subjects, a renal MRI/CT scan on weeks 12, 24 and 48 following the start of treatment (with a ± 7 window), then every year unless the observation of angiomyolipoma response required a confirmation of a second scan approximately 12 weeks after (and not prior to 8 weeks after), and at the time of the study drug withdrawal. The AML radiological response was assessed following the predefined response criteria. Full Analysis Set included all subjects who received at least one dose of everolimus.
    End point type
    Secondary
    End point timeframe
    Until disease progression, unacceptable toxicity, death, discontinuation from the study or until drug becomes commercially available in Spain or until 20 May 2014
    End point values
    Everolimus
    Number of subjects analysed
    19
    Units: percentage of subjects
        number (not applicable)
    47.37
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events and Serious Adverse Events

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    End point title
    Number of Subjects With Adverse Events and Serious Adverse Events
    End point description
    Safety population included all subjects who received at least one dose of RAD001 and had at least one post-baseline safety assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 16 months
    End point values
    Everolimus
    Number of subjects analysed
    19
    Units: subjects
        Adverse events
    19
        Serious adverse events
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until 28 days following the last dose of study treatment.
    Adverse event reporting additional description
    Any sign or symptom that occurs during study treatment plus the 28 days post-treatment
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    Everolimus was administered following an oral daily continuous regimen of two 5 milligram (mg) tablets (10 mg, total daily dose) once a day at the same time everyday, either always with food or without food.

    Serious adverse events
    Everolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Everolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 19 (31.58%)
         occurrences all number
    6
    Dizziness
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Surgical and medical procedures
    Polypectomy
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian cyst
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    7
    Asthenia
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Mucosal dryness
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    5
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    Menstrual disorder
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    3
    Menorrhagia
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Dysmenorrhoea
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Transaminases increased
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Blood cholesterol increased
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Microcytosis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    4
    Pharyngitis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Sciatica
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Chalazion
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Eyelid oedema
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrointestinal disorders
    Aphthous ulcer
         subjects affected / exposed
    7 / 19 (36.84%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    4
    Dysgeusia
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Gingival abscess
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrointestinal pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Odynophagia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    5
    Dermatitis
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Erythema
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Alopecia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    9 / 19 (47.37%)
         occurrences all number
    11
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 19 (26.32%)
         occurrences all number
    8
    Decreased appetite
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    8
    Oral herpes
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    Gingivitis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Ear lobe infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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