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    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2008-000498-40
    Sponsor's Protocol Code Number:CRAD001N2301
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-07-23
    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 ConcernedGermany - BfArM
    A.2EudraCT number2008-000498-40
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, multicenter phase III study of RAD001 adjuvant therapy in poor risk patients with Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 versus matching placebo after patients have achieved complete response with first-line rituximab-chemotherapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized, double-blind, placebo-controlled, multicenter phase III study of RAD001 adjuvant therapy in poor risk patients with Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 versus matching placebo after patients have achieved complete response with first-line rituximab-chemotherapy
    A.4.1Sponsor's protocol code numberCRAD001N2301
    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 Pharma GmbH
    B.5.2Functional name of contact pointMedizinische Infoservice (MCC)
    B.5.3 Address:
    B.5.3.1Street AddressRoonstraße 25
    B.5.3.2Town/ cityNürnberg
    B.5.3.3Post code90429
    B.5.3.4CountryGermany
    B.5.4Telephone number+491802232300
    B.5.5Fax number+4991127312160
    B.5.6E-mailinfoservice.novartis@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
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRAD001
    D.3.2Product code RAD001, 5 mg Tablets
    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 159351696
    D.3.9.2Current sponsor codeRAD001
    D.3.9.3Other descriptive nameEverolimus
    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
    Diffuse Large B-Cell Lymphoma
    E.1.1.1Medical condition in easily understood language
    Diffuse Large B-Cell Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare disease-free survival (DFS) in poor risk patients with DLBCL after achieving CR following first-line R-chemotherapy who receive RAD001 versus patients who receive matching placebo.
    E.2.2Secondary objectives of the trial
    • To compare overall survival (OS) and lymphoma-specific survival (LSS) in patients who receive RAD001 versus patients who receive matching placebo.
    • To describe the safety profile of RAD001 in comparison to the matching placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with previous histologically confirmed Stage III-IV (or Stage II bulky disease, defined as any tumor mass more than 10 cm in longest diameter), at time of original diagnosis, diffuse large B cell lymphoma (pathology report based on original tumor tissue/lymph node is acceptable for meeting inclusion criteria, but tumor tissue (slides/block) must be available to be sent for central pathology to confirm diagnosis).
    2. Patients defined as poor risk with IPI of 3, 4, or 5 at time of original diagnosis.
    3. Patients age ≥ 18 years old.
    4. Patients must have achieved complete remission (CR) based on the revised IWRC (Cheson et al 2007) following first line R-chemotherapy treatment. Radiation therapy (RT) during or after R-chemotherapy is acceptable provided: 1) it ends 4 weeks prior to start of study drug and, 2) in case of consolidation RT targeted at initial bulky tumor mass administered after R-chemotherapy, patient is already in CR before initiating RT. Complete remission from R-chemotherapy must be confirmed by clinical and radiologic evaluation along with bone marrow confirmation (if bone marrow was involved by lymphoma before the R-chemotherapy treatment). Local pathology report on the bone marrow biopsy is acceptable. If bone marrow was not involved by lymphoma before R-chemotherapy treatment, then another bone marrow confirmation after R-chemotherapy is not required.
    5. Patients who received a minimum 5 cycles of R-chemotherapy treatment and maximum 8 cycles of R-chemotherapy treatment. Any variation of R-CHOP interval (R-CHOP-14, R-CHOP-21) is acceptable. Liposomal doxorubicin, epirubicin, or pirarubicin (also known as therarubicin) is acceptable. R-EPOCH is acceptable.
    6. Patients’ last treatment cycle with R-chemotherapy must be 6 to 14 weeks prior to start of study drug.
    7. Patients with ECOG performance status (PS) 0, 1, or 2.
    8. Patients willing to provide a portion of his/her tumor tissue from original diagnosis or lymph node to confirm diagnosis.
    9. The following laboratory values obtained ≤ 21 days prior to start of study drug:
    • Absolute neutrophil count ≥1000/mm3 (or 1.0 GI/L, SI units)
    • Platelet count ≥100,000/mm3 (or 100 GI/L, SI units)
    • Hemoglobin ≥9 g/dL (may be achieved by transfusion)
    • Total bilirubin ≤2 x ULN (if >2 x ULN direct bilirubin is required and should be ≤1.5 x ULN)
    • AST ≤3 x ULN
    • Serum creatinine ≤ 2 x ULN
    10. Women of childbearing potential must have had a negative serum pregnancy test 14 days prior to the start of study drug plus a negative local urine pregnancy test on Day 1, Cycle 1 prior to treatment and must be willing to use highly effective methods of contraception during the study and for 8 weeks after study drug administration.
    11. Patients who give a written informed consent obtained according to local guidelines.
    12. Patients capable of swallowing intact study medication tablets and following directions regarding taking study drug, or have a daily caregiver who will be responsible for administering study drug.
    E.4Principal exclusion criteria
    1. Patients with evidence of disease according to the revised IWRC (Cheson et al 2007) after completion of the first-line R-chemotherapy treatment, prior to study entry.
    2. Patients receiving ongoing radiation therapy or who received radiation therapy to the residual tumor masses <4 weeks from start of study drug.
    3. Patients who have previously received systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus, etc).
    4. Patients with evidence of current central nervous system (CNS) involvement with lymphoma. Patients who have only had prophylactic intrathecal chemotherapy against CNS disease are eligible.
    5. Patients with transformed follicular lymphoma.
    6. Patients who received ibritumomab tiuxetan (Zevalin®), in order, to avoid potential delayed kidney toxicities.
    7. Patients who had myelosuppressive chemotherapy or biologic therapy < 3 weeks from start of study drug.
    8. Patients receiving chronic systemic immunosuppressive agents. Inhaled and topical steroids are acceptable. Patients may be receiving stable (not increased within the last month) chronic doses of corticosteroids with a maximum dose of 20 mg of prednisone or ≤ 5 mg of dexamethasone per day, if they are being given for disorders other than lymphoma such as rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency or asthma.
    9. Patients with active, bleeding diathesis.
    10. Patients with a known history of HIV seropositivity.
    11. Patients with known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to any of its excipients.
    12. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
    • unstable angina pectoris, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 6 months prior to first study drug, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ≤ 6 months before study drug start
    • severely impaired lung function as defined as spirometry and DLCO that is ≤ 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
    • poorly controlled diabetes as defined by fasting serum glucose >2.0 x ULN
    • any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study
    • nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study drug, such as severe hypertension that is not controlled with medical management and thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication
    • liver disease such as cirrhosis or decompensated liver disease
    13. Patients who have a history of another primary malignancy ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of uterine cervix.
    14. Female patients who are pregnant or breast feeding, or of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 8 weeks after study drug administration. Highly effective contraception methods include:
    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
    • Combination of any two of the following (a+b or a+c, or b+c):
    a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
    b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
    In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
    15. Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study drug start.
    16. Patients unwilling to or unable to comply with the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    - Disease-free survival (DFS): Disease-free survival (DFS) is the time from date of randomization to the date of event defined as the first documented recurrence of the disease or death due to any cause.
    E.5.1.1Timepoint(s) of evaluation of this end point
    All DFS events to be included up to 31-Dec-2015
    E.5.2Secondary end point(s)
    1. Overall survival (OS): Overall survival is defined as the time from date of randomization to date of death due to any cause. If the patient is not known to have died, survival will be censored at the date of the last contact
    2. Lymphoma-specific survival (LSS): Lymphoma-specific survival is defined as time from randomization to death as a result of lymphoma, which means that death must be recorded as a result of lymphoma.
    3. Number of adverse events in patients who recieve RAD001 in comparison to matching placebo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    •If Final DFS analysis is significant: Interim OS analysis will be done at
    the time of revised final DFS analysis (31-Dec-2015 cutoff date). If this
    OS analysis is not significant, OS will be tested again at the final OS
    analysis at the pre-defined fixed cut-off date of 31-Dec-2018 (5 years
    after last patient was randomized).
    •If Final DFS analysis is Not significant: OS will not be tested and the
    study close-out activities will be initiated.
    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 No
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA73
    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
    Argentina
    Australia
    Austria
    Brazil
    Canada
    China
    Colombia
    Czech Republic
    Egypt
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Lebanon
    Mexico
    New Zealand
    Norway
    Peru
    Poland
    Russian Federation
    Saudi Arabia
    Singapore
    Slovakia
    Spain
    Switzerland
    Thailand
    Turkey
    United States
    Venezuela, Bolivarian Republic of
    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 years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days25
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months5
    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: 393
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 349
    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
    In cases where the patient’s representative gives consent, the patient should be informed about the study to the extent possible given his/her understanding.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 234
    F.4.2.2In the whole clinical trial 487
    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 Decision2009-08-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-10-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-06-15
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