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    Summary
    EudraCT Number:2008-002113-48
    Sponsor's Protocol Code Number:CRAD001M2302
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-04-02
    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 ConcernedNetherlands - Competent Authority
    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.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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    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 Information not present in EudraCT
    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 159351696
    D.3.9.2Current sponsor codeRAD001
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10051810
    E.1.2Term Angiomyolipoma
    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 or sporadic lymphangioleiomyomatosis.
    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 the duration of angiomyolipoma response, the time to 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.
    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).
    3. Clinically definite diagnosis of renal angiomyolipoma.
    4. Presence of at least one angiomyolipoma ≥ 3 cm in its longest diameter using 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 adequate contraceptive measures, excluding estrogen containing contraceptives, while on study.
    E.4Principal exclusion criteria
    1. Angiomyolipoma-related bleeding or embolization during the 6 months prior to randomization.
    2. History of myocardial infarction, angina or stroke related to atherosclerosis.
    3. Impaired lung function, defined as any of the following:
    • FEV1 ≤ 70% of predicted, or
    • DLCO ≤ 70% of predicted, or
    • ≤ 88% O2 saturation at rest in room air.
    4. Chylous ascites sufficient to affect diaphragmatic function or pulmonary function testing.
    5. 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 < 1,000/mm3).
    6. Pregnancy or breast feeding.
    7. Use of estrogen containing medications.
    8. Intercurrent infection at date of randomization.
    9. Prior history of organ transplant.
    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 MR 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.
    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 at least 4 weeks later.
    In addition, response requires that:
    • no new angiomyolipomata ≥ 1.0 cm in longest diameter are identified
    • that 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])
    • that the patient does not have any angiomyolipoma-related bleeding of grade 2 or worse (as defined by the National Cancer Institute’s (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0 (http://ctep.cancer.gov/forms/CTCAEv3.pdf)).
    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 No
    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 Information not present in EudraCT
    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.8.3 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 Information not present in EudraCT
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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 years6
    E.8.9.1In the Member State concerned months
    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.1.3Elderly (>=65 years) Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Parents or legal guardians must sign the informed consent for patients with developmental delays.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 58
    F.4.2.2In the whole clinical trial 99
    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 Decision2009-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-03-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-09-03
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