Clinical Trials Register

Summary
EudraCT Number:	2015-004824-77
Sponsor's Protocol Code Number:	27UCS2015
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-08
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

Austria - BASG

A.2

EudraCT number

2015-004824-77

A.3

Full title of the trial

A randomized, phase II, double-blind, placebo-controlled, multicenter, 2x2 factorial design biomarker tertiary prevention trial of low-dose aspirin and metformin in stage I-III colorectal cancer patients. The ASAMET Trial

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A biomarker tertiary prevention trial of low-dose aspirin and metformin in stage I-III colorectal cancer patients. The ASAMET Trial

A.3.2

Name or abbreviated title of the trial where available

ASAMET

A.4.1

Sponsor's protocol code number

27UCS2015

A.5.4

Other Identifiers

Name:

ABCSG

Number:

ABCSG C09

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	Ente Ospedaliero Ospedali Galliera Genova
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	E.O. Ospedali Galliera
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	FWF
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	E.O. Ospedali Galliera
B.5.2	Functional name of contact point	Ufficio Coordinatore Scientifico
B.5.3	Address:
B.5.3.1	Street Address	Via Volta, 8
B.5.3.2	Town/ city	Genova
B.5.3.3	Post code	16128
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390105634188
B.5.5	Fax number	00390105748105
B.5.6	E-mail	ucs@galliera.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	Cardioaspirin 100 mg Gastro-resistant tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer HealthCare
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	Aspirin protect / Aspirin Cardio
D.3.2	Product code	BAY e 4465 / acetylsalicylic acid /
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Buccal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
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	100
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	METFORAL 850 mg film coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratori Guidotti S.p.A.
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	METFORAL 850 mg
D.3.2	Product code	AIC: 019449038
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Buccal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMIN HYDROCHLORIDE
D.3.9.1	CAS number	1115-70-4
D.3.9.4	EV Substance Code	SUB03200MIG
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Buccal use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Buccal tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Surgical resected colorectal cancer (stage I-III)

E.1.1.1

Medical condition in easily understood language

Surgical resected colorectal cancer (stage I-III)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To test the synergistic effect of the combined treatment with low dose ASA plus MET given for 1 year to reduce the expression of NFκB (primary endpoint) in unaffected colonic tissue in patients with removed CRC.

E.2.2

Secondary objectives of the trial

1. To test the effect of treatment with ASA and MET, in combination and independently, on the following secondary endpoints:
•The change in IHC expression levels of pS6K, p53, beta-catenin, PI3K
•The change in the circulating biomarkers IL-6, CRP, VEGF and HOMA index
•The gene expression levels of candidate genes , pathways and genome-wide expression profile in colon unaffected biopsy tissue.
2. To define the blood and tissue drug levels of metformin,
3. To genetically characterize the primary colorectal carcinomas using NGS + determine their association with treatment response.
4. To study the treatment tolerability comparing incidence and grade of toxicities among arms
5. To study the serum concentrations of TBx as a biomarker of treatment adherence,to be correlated with biomarker modulation and toxicity.
6. To evaluate the effect of treatment on psychological variables and cancer related fatigue.
7. To evaluate the occurrence of adenoma at baseline + after 12 months

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

In a patient subset (all Italian patients) we will also perform the following analyses:
• Metabolome analysis: the change of low molecular weight compounds in serum samples (up to 53 analytes) to obtain a signature of response to therapy.
• The 12 month change of microbial composition by sequencing of the 16S rRNA gene of the colorectal microbiota by NGS analysis in colonic tissue and faeces.
• The 12 month change in autoantibody compositions in serum samples (ASMA, AMA, APCA, ANA, ANCA, ASCA, ENA/dsDNA, TPO) by ELISA,chemoluminescence and immunoblotting assays.
• To evaluate the interactions between treatment and physical activity, life style and food habits on the endpoint biomarkers.

E.3

Principal inclusion criteria

• Patients aged > 18 and ≤ 80 years.
• Patients with completely resected stage I, II, or III primary colorectal cancer within 24 months prior to randomization, regardless of (neo-)adjuvant chemotherapy. Patientswith pT1 CRC treated with endoscopic polypectomy.
• Adjuvant chemotherapy and (neo)adjuvant radiotherapy terminated at least 3 months before randomization.
• ECOG performance status ≤ 1.
• Satisfactory hematological and biochemical functions:
o Platelets ≥ 100 x 10^9/L
o Creatinine clearance estimated with the Cockcroft - Gault formula ≥ 60 mL/min. Patients with Gault formula ≥ 30-≤ 59 ml/min are eligible but they will receive a single (evening) tablet of MET, 850 mg.
o AST and ALT ≤ 2.5 times ULN.
• Females of childbearing potential/males with partners of childbearing potential participating in the study are to use effective methods of birth control during study participation. Female participants must provide a pregnancy test, according to local national guidelines.
• Able to understand and sign an informed consent (or have a legal representative who is able and willing to do so).

E.4

Principal exclusion criteria

• Patients who are not able to undergo colonoscopy.
• Patients who are allergic or intolerant to ibuprofen or naproxen, or who have MET-, or ASA-, or salicylate intolerance or more generalized drug intolerance to non-steroidal anti-inflammatory drugs (NSAIDs).
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with study procedures.
• Chronic treatment with ASA or other NSAIDs or MET or patients who are on current long term treatment (≥ 4 consecutive weeks) with ASA, NSAID or COX -2 inhibitors or MET.
• Diabetic patients on drug treatment are excluded.
• Anticoagulant therapy (dicumarol, heparin, fondaparinux, apixaban, dabigatran etexilate, rivaroxaban) or active current treatment with antiplatelet agents (e.g. off-study ASA, clopidogrel, prasugrel, ticagrelor, or ticlopidine).
• Any other invasive malignancies (with the exclusion of basal cell carcinoma or cutaneous squamous cell carcinoma) diagnosed during the last 5 years before randomization.
• Past history of any other invasive CRC than the one the patient is currently being treated for
• Alcohol or drug abuse, defined according to Investigators discretion.
• Prior history of gastro-intestinal bleeding to ASA or hemorrhagic diathesis (e.g. hemophilia).
• Erosive-ulcerative lesions in the gastrointestinal tract
• History of erosive GERD or active erosive GERD on gastroscopy.
• Concomitant corticosteroid treatment.
• Known hypersensitivity or intolerance to MET or ASA or NSAID.
• Deficiency of glucose-6-phosphate dehydrogenase (G6PD).
• Treatment with another investigational drug < 28 days prior to study entry.
• Concurrent participation in a clinical trial with the same endpoints.
• History of hemorrhagic stroke.
• Lynch Syndrome (HNPCC).
• Crohn's disease (CD) and Ulcerative Colitis (UC).
• Pregnant or lactating females.
• History of lactic acidosis.
• Liver dysfunction including chronic active hepatitis and cirrhosis not compensated.
• History of vitamin B12 deficiency or megaloblastic anemia.
• Uncontrolled coronary syndrome or symptomatic congestive heart failure (e.g. Class III or IV New York Heart Association's Functional Classification).
• Inability or unwillingness to swallow tablets.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

1. To test the effect of treatment with ASA and MET, in combination and independently, on the following secondary endpoints:
•The change in IHC expression levels of pS6K, p53, beta-catenin, PI3K
•The change in the circulating biomarkers IL-6, CRP, VEGF and HOMA index
•The gene expression levels of candidate genes , pathways and genome-wide expression profile in colon unaffected biopsy tissue.
2. To define the blood and tissue drug levels of metformin,
3. To genetically characterize the primary colorectal carcinomas using NGS
and determine their association with treatment response.
4. To study the treatment tolerability comparing incidence and grade of toxicities among arms
5. To study the serum concentrations of TBx as a biomarker of treatment adherence,to be correlated with biomarker modulation and toxicity.
6. To evaluate the effect of treatment on psychological variables and cancer related fatigue.
7. To evaluate the occurrence of adenoma (low, intermediate and/or high grade intraepithelial neoplasia) at baseline and 12 months after randomization acc. to the Vienna classification of gastrointestinal epithelial neoplasia.

E.5.2.1

Timepoint(s) of evaluation of this end point

T0 (basal), T1 (12 months of treatment)

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

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

Yes

E.6.13.1

Other scope of the trial description

tertiary prevention

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

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

2X2 factorial

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.7

Trial 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

6 months after the LVLS (for last patient Biomarker Assessment, Data Cleaning & Data Base Closure)

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

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

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

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

160

F.4.2.2

In the whole clinical trial

160

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	University Medical Centre Ljubljana (UMCL) – Japljeva 2
G.4.3.4	Network Country	Slovenia
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Austrian Breast & Colorectal Cancer Study Group (ABCSG)
G.4.3.4	Network Country	Austria
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	University Hospital Heidelberg
G.4.3.4	Network Country	Germany
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	University Medical Center Johannes Gutenberg-Universität Mainz
G.4.3.4	Network Country	Germany

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-01-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-29

P. End of Trial
P.	End of Trial Status	Completed

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