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    Summary
    EudraCT Number:2008-002113-48
    Sponsor's Protocol Code Number:CRAD001M2302
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-05-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2008-002113-48
    A.3Full title of the trial
    A randomized double-blind, placebo-controlled study of RAD001 in the treatment of Angiomyolipoma in patients with either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety of RAD001 in patients aged 18 and over with Angiomyolipoma associated with either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
    A.3.2Name or abbreviated title of the trial where available
    EXIST-2
    A.4.1Sponsor's protocol code numberCRAD001M2302
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharmaceuticals UK Limited
    B.5.2Functional name of contact pointMedical Collaboration Centre
    B.5.3 Address:
    B.5.3.1Street AddressFrimley Business Park
    B.5.3.2Town/ cityFrimley, Camberley, Surrey
    B.5.3.3Post codeGU16 7SR
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number441276698370
    B.5.5Fax number441276698449
    B.5.6E-mailmedinfo.uk@novartis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Afinitor 5mg Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europham Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/10/764
    D.3 Description of the IMP
    D.3.1Product nameRAD001
    D.3.2Product code RAD001
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.2Current sponsor codeRAD001
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Angiomyolipoma in patients with either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
    E.1.1.1Medical condition in easily understood language
    Angiomyolipoma in patients with either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10051810
    E.1.2Term Angiomyolipoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the angiomyolipoma response rate on RAD001 versus placebo in patients with angiomyolipoma, associated with either tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM).
    E.2.2Secondary objectives of the trial
    To compare RAD001 versus placebo with respect to:
    1. Time to angiomyolipoma progression.
    2. Skin lesion response rate.
    3. Change from baseline in plasma angiogenic molecules, e.g. VEGF, basic FGF, PLGF, soluble VEGF receptor1, and soluble VEGF receptor2.
    4. Renal function assessed using calculated creatinine clearance.
    5. Safety as assessed by the National Cancer Institute’s (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0.
    In RAD001 treatment arm to:
    1. Characterize the pharmacokinetics of RAD001 in this patient population, specifically in terms of exposure.
    2. Describe time to angiomyolipoma response, the duration of angiomyolipoma response and the duration of skin lesion response.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ≥ 18 years of age.
    2. Clinically definite diagnosis of tuberous sclerosis according to the modified Gomez criteria (Roach et al, 1998; Hyman and Whittemore, 2000) or sporadic LAM (biopsy-proven or compatible chest CT scan).
    3. Clinically definite diagnosis of renal angiomyolipoma.
    4. Presence of at least one angiomyolipoma ≥ 3 cm in its longest diameter using CT or MRI.
    5. If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment. Sexually active pre-menopausal female patients (and female partners of male patients) must use highly effective contraceptive measures, while on study and for 8 weeks after ending treatment.
    6.Written informed consent according to local guidelines.

    Non-interventional follow-up phase:
    1. No angiomyolipoma progression at time of study treatment
    discontinuation and no plan to continue treating their
    angiomyolipoma(s) with systemic therapy
    2. Non-interventional follow-up phase consent
    Other protocol-defined inclusion criteria may apply.
    E.4Principal exclusion criteria
    1. Patients with angiomyolipomas which, in the opinion of the investigator, requires surgery at the tiem of randomization.
    2-Angiomyolipoma-related or embolization during the 6 months prior to randomization.
    3. History of myocardial infarction, angina or stroke related to atherosclerosis.
    4. Impaired lung function, defined as any of the following:
    For patients without lymphangioleiomyomatosis (LAM)
    Known impaired lung function (e.g.FEV1 or DLco ≤ 70% of predicted)
    For patients with lymphangioleiomyomatois (LAM)
    • DLCO ≤ 35%, or
    • O2 saturation below normal at rest, or
    • O2 saturation ≤ 88% on 6 minute walking test with up to 6 litre O2/min nasal oxygen
    5. Chylous ascites sufficient to affect diaphragmatic function or pulmonary function testing.
    6. Significant hematological or hepatic abnormality (i.e., transaminase levels > 2.5 × the upper limit of normal (ULN), serum bilirubin > 1.5 × ULN, hemoglobin < 9g/dL, platelets < 80,000/mm3, or absolute neutrophil count (ANC) < 1,000/mm3).
    7. Pregnancy or breast feeding.
    8. Intercurrent infection at date of randomization.
    9. Prior history of organ transplantation.
    10. Recent surgery (involving entry into a body cavity or requiring sutures) within the 2 months prior to randomization.
    11. Prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus).
    12. Use of an investigational drug within the 30 days prior to randomization.
    13. Uncontrolled hyperlipidemia: Fasting serum cholesterol > 300 mg/dL (or > 7.75 mmol/L AND fasting triglycerides > 2.5 × ULN.
    14. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 × ULN.
    15. Patients with bleeding diathesis or on oral anti-vitamin K medication (except low dose warfarin).
    16. Patients with a known history of HIV seropositivity.
    17. Inability to attend scheduled clinic visits.
    18. For the purpose of MRI assessments:
    • Ferromagnetic metal implants other than those approved as safe for use in MRI scanner (e.g., braces, some types of aneurysm clips, shrapnel).
    • Patients suffering from uncontrollable claustrophobia or physically unable to fit into the machine (e.g., obesity, etc).
    19. Serum creatinine > 1.5 × ULN.
    20. History of malignancy in the past two years, other than squamous or basal cell skin cancer.
    21. Any severe and/or uncontrolled medical conditons which could cause unacceptable safety risks or compromise compliance with the protocol.

    Non-interventional follow-up phase:
    1. Starting treatment with any mTOR inhibitor
    2. Embolization immediately after discontinuing study treatment
    3. Surgical resection of angiomyolipoma after discontinuing study
    treatment
    4. Prior kidney CT/MRI already performed 1-year after discontinuation of
    everolimus
    Other protocol-defined exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Angiomyolipoma response rate is defined as the proportion of patients with a reduction in angiomyolipoma volume of at least 50% relative to baseline, where angiomyolipoma volume is the sum of the volumes of all target angiomyolipomata identified at baseline, and confirmed with a second scan approximately 12 weeks later (and no sooner than 8 weeks later).
    In addition, response requires that:
    • no new angiomyolipomata ≥ 1.0 cm in longest diameter are identified
    • neither kidney increases in volume by more than 20% from nadir (where nadir is the lowest kidney volume obtained for the patient, separately for each kidney, previously during the trial [including baseline])
    • the patient does not have any angiomyolipoma-related bleeding of grade ≥ 2 (as defined by the NCI CTCAE, version 3.0 (http://ctep.cancer.gov/forms/CTCAEv3.pdf)).
    E.5.1.1Timepoint(s) of evaluation of this end point
    From date of randomization until the earliest date of first documented
    AML progression, date of further anti-AML medication (including openlabel
    Everolimus)/surgery or analysis cut-off date (30-June-2011)
    E.5.2Secondary end point(s)
    1. Time to Angiomyolipoma Progression as Per Central Radiology Review
    (Double-blind Period)
    2. Skin Lesion Response Rate as Per Investigator (Only Patients With at
    Least One Skin Lesion at Baseline)
    3. Percentage of Participants With Renal Impairment
    4. Change From Baseline in Plasma Angiogenic Molecules
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 2 & 3. From date of randomization until the earliest date of first documented
    AML progression, date of further anti-AML medication (including openlabel
    Everolimus)/surgery or analysis cut-off date (30-June-2011)
    4. Baseline, 12 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers analyses
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Japan
    Russian Federation
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 101
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 63
    F.4.2.2In the whole clinical trial 118
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Please refer to the protocol.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-06-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-08-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-11-06
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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