Clinical Trials Register

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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2020-002579-37

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

Metformin-Bone

Metformina-Bone

A.4.1

Sponsor's protocol code number

Metformina-Bone

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ISTITUTO ORTOPEDICO RIZZOLI
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS Istituto Ortopedico Rizzoli
B.5.2	Functional name of contact point	SSD Chemioterapia dei tumori dell'a
B.5.3	Address:
B.5.3.1	Street Address	Via G. C. Pupilli 1
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40136
B.5.3.4	Country	Italy
B.5.4	Telephone number	0516366411
B.5.5	Fax number	0516366277
B.5.6	E-mail	alessandra.longhi@ior.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ZUGLIMET - 500 MG COMPRESSE RIVESTITE CON FILM 30 COMPRESSE IN BLISTER PVC/AL
D.2.1.1.2	Name of the Marketing Authorisation holder	ZENTIVA ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Zuglimet cpr riv 500 mg
D.3.2	Product code	[038257022]
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMINA CLORIDRATO
D.3.9.2	Current sponsor code	Metformina cloridrato
D.3.9.3	Other descriptive name	Metformin hydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Metformina cloridrato
D.3.9.2	Current sponsor code	Metformina cloridrato
D.3.9.3	Other descriptive name	metformin hydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ZUGLIMET - 850 MG COMPRESSE RIVESTITE CON FILM 40 COMPRESSE IN BLISTER PVC/AL
D.2.1.1.2	Name of the Marketing Authorisation holder	ZENTIVA ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Zuglimet cpr riv 850 mg
D.3.2	Product code	[038257085]
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMINA CLORIDRATO
D.3.9.2	Current sponsor code	Metformina cloridrato
D.3.9.3	Other descriptive name	Metformin hydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	850
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Osteosarcoma and Ewing's Sarcoma

Osteosarcoma e Sarcoma di Ewing

E.1.1.1

Medical 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.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10023676
E.1.2	Term	Lactic acidosis
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10000491
E.1.2	Term	Acidosis lactic
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

E.3

Principal 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.4

Principal 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.5.1

Primary 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.5.1.1

Timepoint(s) of evaluation of this end point

3 years

3 anni

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Children

Minori

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-10-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-11-18

P. End of Trial
P.	End of Trial Status	Ongoing

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