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    Summary
    EudraCT Number:2020-002579-37
    Sponsor's Protocol Code Number:Metformina-Bone
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-22
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-002579-37
    A.3Full title of the trial
    Metformin as maintenance therapy in bone sarcomas at high risk of relapse
    Metformina come terapia di mantenimento in sarcomi ossei ad alto rischio di ricaduta
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Administration of Metformin as maintenance therapy in patients with osteosarcoma or Ewing's sarcoma
    Somministrazione di Metformina come terapia di mantenimento in pazienti con osteosarcoma o sarcoma di Ewing
    A.3.2Name or abbreviated title of the trial where available
    Metformin-Bone
    Metformina-Bone
    A.4.1Sponsor's protocol code numberMetformina-Bone
    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 SponsorISTITUTO ORTOPEDICO RIZZOLI
    B.1.3.4CountryItaly
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS Istituto Ortopedico Rizzoli
    B.5.2Functional name of contact pointSSD Chemioterapia dei tumori dell'a
    B.5.3 Address:
    B.5.3.1Street AddressVia G. C. Pupilli 1
    B.5.3.2Town/ cityBologna
    B.5.3.3Post code40136
    B.5.3.4CountryItaly
    B.5.4Telephone number0516366411
    B.5.5Fax number0516366277
    B.5.6E-mailalessandra.longhi@ior.it
    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 ZUGLIMET - 500 MG COMPRESSE RIVESTITE CON FILM 30 COMPRESSE IN BLISTER PVC/AL
    D.2.1.1.2Name of the Marketing Authorisation holderZENTIVA ITALIA S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameZuglimet cpr riv 500 mg
    D.3.2Product code [038257022]
    D.3.4Pharmaceutical form 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 INNMETFORMINA CLORIDRATO
    D.3.9.2Current sponsor codeMetformina cloridrato
    D.3.9.3Other descriptive nameMetformin hydrochloride
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMetformina cloridrato
    D.3.9.2Current sponsor codeMetformina cloridrato
    D.3.9.3Other descriptive namemetformin hydrochloride
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 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.IMP: 2
    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 ZUGLIMET - 850 MG COMPRESSE RIVESTITE CON FILM 40 COMPRESSE IN BLISTER PVC/AL
    D.2.1.1.2Name of the Marketing Authorisation holderZENTIVA ITALIA S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameZuglimet cpr riv 850 mg
    D.3.2Product code [038257085]
    D.3.4Pharmaceutical form 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 INNMETFORMINA CLORIDRATO
    D.3.9.2Current sponsor codeMetformina cloridrato
    D.3.9.3Other descriptive nameMetformin hydrochloride
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number850
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Osteosarcoma and Ewing's Sarcoma
    Osteosarcoma e Sarcoma di Ewing
    E.1.1.1Medical condition in easily understood language
    Osteosarcoma: a rare malignant tumor that arises from bone cells.
    Ewing's sarcoma: a malignant bone tumour with a strong metastatic potential.
    Osteosarcoma: tumore maligno raro che nasce dalle cellule ossee.
    Sarcoma di Ewing: tumore maligno dell'osso con un forte potenziale metastatico.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10023676
    E.1.2Term Lactic acidosis
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10000491
    E.1.2Term Acidosis lactic
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of EFS (Event Free Survival) in patients with osteosarcoma and Ewing's Sarcoma at high risk of relapse compared to that found in historical controls.
    Valutazione dell'EFS (Event Free Survival) in pazienti con osteosarcoma e Sarcoma di Ewing ad alto rischio di ricaduta rispetto a quella rilevata in controlli storici.
    E.2.2Secondary objectives of the trial
    Evaluate metformin toxicity (blood tests, clinical evaluation), compliance of therapy with EORTC QLQ C-30 questionnaire for adults based on age.
    Valutare la tossicità della metformina (esami ematici, valutazione clinica), la compliance della terapia con questionario EORTC QLQ C-30 per adulti in base all'età.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age = 14 years
    - Patients with localized osteosarcoma with necrosis = 60% at the end of postoperative chemotherapy (within 45 days)
    - Patients with osteosarcoma or Ewing's Sarcoma made disease-free after the first relapse (within 45 days of surgery or chemotherapy)
    - Patients not included in other protocols
    - Patients who can swallow
    - Screening within 30 days after the end of chemotherapy (or relapse surgery).
    - Start of treatment within 30 minutes after screening
    - Normal renal function (creatinine <1.3, creatinine > 60) and liver function (serum bilirubin <1.4, AST and ALT <1.8) above the normal range.
    - Età = 14 anni
    - Pazienti con osteosarcoma localizzato con necrosi = 60% al termine della chemioterapia postoperatoria (entro 45 giorni dal termine)
    - Pazienti con osteosarcoma o Sarcoma di Ewing reso libero da malattia dopo la prima ricaduta (entro 45 gg da chirurgia o termine chemioterapia)
    - Pazienti non inseriti in altri protocolli
    - Pazienti in grado di deglutire
    - Screening entro 30 gg dal termine della chemioterapia (o dalla chirurgia per ricaduta
    - Inizio trattamento entro 30 dallo screening
    - Normale funzionalità renale (creatinina <1,3, creatinina > 60) e funzionalità epatica (Bilirubina sierica <1,4, AST e ALT <1,8) con valore superiore al range normale.
    E.4Principal exclusion criteria
    - Type I or II diabetes
    - Patient with metastatic disease
    - Patients with kidney failure of any degree
    - Patient who does not meet the inclusion criteria
    - Diabete di tipo I o II
    - Paziente con malattia metastatica
    - Pazienti con insufficienza renale di qualsiasi grado
    - Paziente che non rientra nei criteri di inclusione
    E.5 End points
    E.5.1Primary end point(s)
    - In cohort 1 (localized osteosarcomas with poor necrosis) increase EFS to 3 years from 35% (personal case references) to 60%.

    - In cohort 2 (patients made disease-free after relapse both osteosarcomas and Ewing's sarcomas) increase Post Relapse Disease Free Survival (PRDFS) to 1 year after achieving complete post- relapse remission from 20% (historical references) to 45%.
    - Nella coorte 1 (osteosarcomi localizzati con necrosi scarsa) portare l’EFS a 3 anni dal 35% (riferimenti casistica personale) al 60%.

    - Nella coorte 2 (pazienti resi liberi da malattia dopo ricaduta sia osteosarcomi che sarcomi di Ewing) aumento del Post Relapse Disease Free Survival (PRDFS) a 1 anno dal raggiungimento della remissione completa post ricaduta di malattia dal 20% (riferimenti storici) al 45%.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3 years
    3 anni
    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 No
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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 Information not present in EudraCT
    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
    For Cohort 1 the study will be closed when the 3-year FUP is reached for each patient.
    For Cohort 2 when all patients have reached at least 12 months of treatment or follow-up and then 12 months of interval since the last relapse. In the absence of relapse of disease or toxicity it is recommended to continue taking Metformin for a further 2 aa after the first year (36 months in all).
    Per la Coorte 1 lo studio sarà chiuso al raggiungimento dei 3 anni di FUP per ciascun paziente.
    Per la Coorte 2 quando tutti i pazienti avranno raggiunto almeno 12 mesi di trattamento o follow up e quindi 12 mesi di intervallo dalla ultima ricaduta. In assenza di ricaduta di malattia o tossicità è raccomandato continuare l’assunzione di Metformina per altri 2 aa dopo il primo anno (36 mesi in tutto).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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 years7
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 60
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) No
    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 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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Children
    Minori
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    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)
    Control of lactic acid, glycaemia, creatinine azotemia, after 1 week and then after 7, 15, 28 days then at the 2nd and 3rd month from the beginning of treatment then every 3-4 months in conjunction with follow-up visits or earlier if disturbances appear.
    Controllo dell’acido lattico, glicemia, creatinina azotemia, dopo 1 settimana e poi dopo 7, 15 ,28 giorni poi al 2° e 3° mese dall’inizio trattamento poi ogni 3-4 mesi in concomitanza delle visite di follow up o prima se compaiono disturbi.
    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 Decision2020-10-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-18
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
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