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    Summary
    EudraCT Number:2014-005193-11
    Sponsor's Protocol Code Number:METAL
    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:2015-02-09
    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 number2014-005193-11
    A.3Full title of the trial
    METformin And Longevity (METAL): A window of opportunity study investigating biological effects of metformin in localised prostate cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A window of opportunity study investigating biological effects of metformin in localised prostate cancer
    A.3.2Name or abbreviated title of the trial where available
    METAL
    A.4.1Sponsor's protocol code numberMETAL
    A.5.4Other Identifiers
    Name:REC Number Number:15/LO/0290
    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 SponsorKing's College London
    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 supportJP Moulton Charitable Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKing's College London
    B.5.2Functional name of contact pointDr Sarah Rudman
    B.5.3 Address:
    B.5.3.1Street AddressMedical Oncology, 4th Floor Bermondsey Wing, Guy’s Hospital
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSE1 9RT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4402071887903
    B.5.5Fax number+4402071884271
    B.5.6E-mailsarah.rudman@gstt.nhs.uk
    B.Sponsor: 2
    B.1.1Name of SponsorGuy's and St Thomas' NHS Foundation Trust
    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 supportJP Moulton Charitable Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGuy's and St Thomas' NHS Foundation Trust
    B.5.2Functional name of contact pointDr Sarah Rudman
    B.5.3 Address:
    B.5.3.1Street AddressMedical Oncology, 4th Floor Bermondsey Wing, Guy’s Hospital
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSE1 9RT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4402071887903
    B.5.5Fax number+4402071884271
    B.5.6E-mailsarah.rudman@gstt.nhs.uk
    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 Metformin 500mg Tablets BP
    D.2.1.1.2Name of the Marketing Authorisation holderMedley Pharma Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Film-coated 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 INNMetformin hydrocholride
    D.3.9.1CAS number 1115-70-4
    D.3.9.3Other descriptive nameMetformin
    D.3.9.4EV Substance CodeSUB08831MIG
    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
    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
    Prostate cancer
    E.1.1.1Medical condition in easily understood language
    Cancer of the prostate
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10060862
    E.1.2Term Prostate cancer
    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 determine the biological effect of metformin on markers of the FASN/AMPK pathway in prostate tissue by comparison of pre and post-treatment samples.
    E.2.2Secondary objectives of the trial
    To evaluate the biological effect of metformin on markers of proliferation in prostate tissue by comparison of pre and post-treatment samples.

    To evaluate differences in expression levels of FASN/AMPK-associated biomarkers in benign and malignant prostate tissue

    To measure metformin levels in prostate tissue

    To determine safety of metformin in this non-diabetic patient cohort

    To determine surgical toxicity
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Exploratory End point Sub-study 08.09.2015 Version 5.0
    Objective: To evaluate the effects of metformin on functional imaging of the prostate
    Endpoint: The difference in 18F Choline PET/MRI between baseline and post-treatment (prior to prostatectomy) in a separate non-randomised cohort of five patients with MRI positive disease receiving metformin.
    The criteria for enrolment in to this sub study are:
    1. Patient willing to undergo two additional PET-MRI scans
    2. MRI positive disease
    3. Satisfactory completion of MRI safety questionnaire
    4. Availability of 18F Choline and scanning slots which would not result in a delay to the patients enrolment into the study or to their surgery
    E.3Principal inclusion criteria
    1. Age 18 or older and willing and able to provide signed informed consent.
    2. Histologically confirmed adenocarcinoma of the prostate , with a maximal tumour length of greater or equal to 6mm on core biopsy
    3. No previous treatment for prostate cancer (including surgery, any hormone therapy, radiotherapy and cryotherapy)
    4. Prostate biopsy within 6 months from screening.
    5. Radical prostatectomy is the scheduled treatment of choice
    6. Eastern Cooperative Oncology Group (ECOG) Performance status less than or equal to 0 or 1.
    7. Adequate organ function, defined as follows:
    Haemoglobin >10.0g/dL
    Absolute neutrophil count >1.5x109/L
    Platelet count >100x109/L
    Renal function, eGFR >60ml/min (calculated by Cockcroft Gault)
    AST and/or ALT <2.5 x ULN
    Total Bilirubin <1.5 x ULN
    8. Able to swallow the drug and comply with study requirements.
    E.4Principal exclusion criteria
    1. Patients with a current or historical diagnosis of type one or two Diabetes and/or have ever received metformin
    2. Patients with hypersensitivity to any of the components of Metformin or placebo tablet
    3. History of or conditions associated with lactic acidosis such as shock or pulmonary insufficiency, alcoholism (acute or chronic), and conditions associated with hypoxaemia
    4. Patients with chronic liver disease, severe cardiovascular impairment, cardiac failure, recent myocardial infarction, severe peripheral vascular disease or renal impairment (eGFR <60ml/min as measured by Cockcroft Gault)
    5. Patients with acute severe disorders, for example infections with fever, pancreatitis, trauma, dehydration or reduced diet (<1000kcal or 4200kJ per day)
    6. Other active malignancy over the last five years that has required systemic therapy, excluding:
    a. Adjuvant therapy in the curative setting
    b. Non-melanoma skin cancer
    c. Superficial transitional cell carcinoma (CIS-T1)
    7. Current enrolment in an investigational drug or device study or participation in such a study within 30 days of signing consent.
    8. Any subjects who is able to father a child and does not agree to use barrier protection, in the form of a condom ,for the duration of the trial and for 16 weeks after the last study drug administration.
    E.5 End points
    E.5.1Primary end point(s)
    Assessment of the difference in expression levels of markers of the FASN/AMPK pathway pre and post treatment between the placebo and metformin arms.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be completed pre and post 5 weeks of treatment with the IMP.
    E.5.2Secondary end point(s)
    Assessment of the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms.

    Assessment of the difference in expression levels of markers of the FASN/AMPK pathway and indicators of proliferation between benign and malignant prostate tissue in the placebo and metformin arms.

    Assessment of the difference in metformin levels in baseline and post-treatment prostate tissue.

    Assessment of adverse events and laboratory evaluations.

    Assessment of surgical-specific toxicities: time between biopsy and surgery, peri-operative bleeding, infection, rectal injury and length of hospital stay.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary endpoints will be completed pre and post 5 weeks of treatment with the IMP.
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    Molecular mechanisms
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 No
    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 concerned3
    E.8.5The trial involves multiple Member States No
    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 No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    F.2 Gender
    F.2.1Female No
    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 state105
    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)
    None
    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 Decision2015-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-31
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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