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    Summary
    EudraCT Number:2007-007262-38
    Sponsor's Protocol Code Number:N/A
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-04-30
    Trial 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 number2007-007262-38
    A.3Full title of the trial
    Efficacy of adjuvant mitotane in prolonging recurrence-free survival in patients with adrenocortical carcinoma at low-intermediate risk of recurrence
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of adjuvant mitotane in prolonging recurrence-free survival in patients with adrenocortical carcinoma at low-intermediate risk of recurrence
    A.3.2Name or abbreviated title of the trial where available
    ADIUVO version 1.0
    A.4.1Sponsor's protocol code numberN/A
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00777244
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Birmingham
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCTAAC
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportEuropean Union Seventh Framework Programme (FP7/2007-2013)
    B.4.2CountryEuropean Union
    B.4.1Name of organisation providing supportHRA pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCR UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham
    B.5.2Functional name of contact pointTrial Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressVincent Drive
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214143793
    B.5.5Fax number01214142230
    B.5.6E-maila.i.hughes@bham.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP Role
    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 Lysodren
    D.2.1.1.2Name of the Marketing Authorisation holderHRA Pharma
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameLysodren®
    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 INNMitotane
    D.3.9.1CAS number 0000053-19-0
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Adrenocortical carcinoma
    E.1.1.1Medical condition in easily understood language
    Cancer of the adrenal glands
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10001388
    E.1.2Term Adrenocortical carcinoma
    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
    The primary objective is to compare the efficacy of mitotane treatment vs. observational follow-up only in prolonging survival without disease recurrence in patients with adrenocortical carcinoma at low-intermediate risk of recurrence after complete surgical resection of the tumour.
    E.2.2Secondary objectives of the trial
    The secondary objectives are: - Overall survival - Time to Recurrence - Disease Free Survival - Quality of life assessment - Toxicity assessment - Assessment of the impact of mitotane plasma levels and time needed to reach the therapeutic interval on the efficacy of treatment. - Assessment of the efficacy of the mitotane administration in predefined subgroups of patients stratified according to: - type of hormone secretion - stage of disease - histopathologic characteristics
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed diagnosis of ACC according to Weiss system 2. Low-intermediate risk of relapse defined as: o Stage I-III (according to ENSAT classification 2008) 3. Microscopically complete resection, defined as no evidence of microscopic residual disease based on surgical reports, histopathology and post-operative imaging. Detailed pathological and surgical reports prepared according to guidelines should be available for assessment. 4. Ki 67 </= 10% 5. Post-operative imaging (CT with contrast medium of chest, abdomen and pelvis (or alternatively MRI) demonstrating no evidence of disease within 4 weeks before randomisation 6. Age >/= 18 years 7. ECOG performance status 0-2 8. Adequate bone marrow reserve (neutrophils >/=1000/mm3 and/or platelets >/= 80000/ mm3) 9. Ability to comply with the protocol procedures 10. Written informed consent
    E.4Principal exclusion criteria
    1. Time between primary surgery and randomisation > 3 months. 2. Repeated surgery for recurrence of disease 3. Persistence of autonomous adrenocortical hormone secretion following surgery. 4. History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least three years 5. Renal insufficiency (creatinine clearance < 40 ml/min). Creatinine clearence may be calculted according to validated formulas (Crockoft’s or MDRD) 6. Liver insufficiency (serum bilirubin > 2 times the upper normal range and/or serum transaminases (AST/SGOT, ALT/SGPT) >3 times the upper normal range). 7. Pregnancy or breast feeding 8. Previous or current treatment with mitotane or other antineoplastic drugs for ACC 9. Previous radiotherapy of the tumour bed for ACC 10. Any other severe acute or chronic medical or psychiatric condition,or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is recurrence free survival (RFS), defined as the time between the date of randomisation until documentation of either of the following events (whichever occurs first): - local or distant recurrence of ACC - death from any cause
    E.5.1.1Timepoint(s) of evaluation of this end point
    it is calculated that 97 events in the primary endpoint RFS should be observed and approximately 184 patients should be randomised considering 4 years of accrual and 2 years of follow-up after entry of the last patient. Assuming a lost-to-follow-up rate of maximum 10%, a total of 200 patients (100 per treatment arm) will be needed. The two interim analyses will be carried out at 20% and 60% of the information rate (that under constant accrual rate correspond to about 2 years observation time and 19 expected events and, 4 years observation time and 58 expected events, respectively) Critical p-values for stopping are determined at p = 0.00001 for the first interim analysis, p = 0.01202 for the second and p = 0.0464 for the final analysis.
    E.5.2Secondary end point(s)
    • Overall Survival, defined as the time interval between the date of randomisation and the date of death from any cause. • Time to recurrence, defined as the time between the date of randomisation and documentation of local or distant recurrence of ACC, or death from ACC (whichever occurs first). • Disease Free Survival, defined as the time interval between the date of randomisation and documentation of any relevant cancer disease, or death of any cause (whichever occurs first). • Quality of life Quality of life will be measured by the standardised EORTC-QLQ-C30 questionnaire. Two measures for the change are dealt with, the change in global quality of life at the time of first evaluation and the average change in global quality of life within the first two years or up to recurrence (whichever occurs first) both in reference to the baseline value. • Toxicity, safety measures that will be used in the study include physical examination and clinical laboratory tests (haematology, blood chemistries and creatinine clearance). Adverse events will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 • Incidence of second primary cancers. • RFS, TTR, DFS and OS in patients who achieve or not plasma mitotane concentrations >/= 14 mg/L. • RFS TTR, DFS and OS in patient subgroups stratified according to: - Type of hormone secretion (cortisol secreting tumours vs. purely sex- hormone secreting tumours vs. non secreting tumours) - Stage of disease (according to the ENSAT classification 2008) - Histopathological characteristics
    E.5.2.1Timepoint(s) of evaluation of this end point
    After patients have been under follow-up monitoring for at least 2 years.
    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 No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Simple observation post surgical excision
    E.8.2.4Number of treatment arms in the trial1
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    For the purposes of the MHRA the end of trial will be 2 months after the last patient has completed protocol treatment . This will allow sufficient time for the completion of protocol procedures, data collection and data input. For the purposes of main REC approval, the trial end date is deemed to be the date of last data capture following 2 years of long-term follow-up.
    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 days0
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 150
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    Mitotane will be administered until ACC relapse, intolerable toxicity or for a period of 2 years. After the end of this period study treatment is stopped the local investigator is free to continue or stop mitotane according to his/her best clinical judgment and patient preference. If the mitotane is stopped and for patients in the observation follow-up only group, the patients'doctor will continue to treat them as per standard of care.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-04-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-20
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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