Clinical Trials Register

Summary
EudraCT Number:	2019-000276-41
Sponsor's Protocol Code Number:	SUMO
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-03-05
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

Netherlands - Competent Authority

A.2

EudraCT number

2019-000276-41

A.3

Full title of the trial

Study on the effects of an OCT2/MATE1 substrate (metformin) and inhibitor (cimetidine) on the exposure of trifluridine/tipiracil (Lonsurf®) in patients with metastatic colorectal cancer (mCRC).

Studie naar de effecten van een OCT2/MATE 1 substraat (metformine) en inhibitor (cimetidine) op de blootstelling van trifluridine/tipiracil (Lonsurf®) bij patiënten met gemetastaseerd colorectaal carcinoom.

A.3.1

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

Study on the effects of metformin and cimetidine on the exposure of trifluridine/tipiracil (lonsurf®) in patients with a metastatic colorectal carcinoma

Studie naar het effect van metformine en cimetidine op de blootstelling van trifluridine/tipiracil (lonsurf®) bij patiënten met gemetastaseerd colorectaal carcinoom.

A.3.2

Name or abbreviated title of the trial where available

SUMO trial

A.4.1

Sponsor's protocol code number

SUMO

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	Erasmus MC
B.1.3.4	Country	Netherlands
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	Servier Nederland Farma B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus MC
B.5.2	Functional name of contact point	Ron H.J. Mathijssen
B.5.3	Address:
B.5.3.1	Street Address	's gravendijkwal 230
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 CE
B.5.3.4	Country	Netherlands
B.5.6	E-mail	a.mathijssen@erasmusmc.nl

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	Lonsurf
D.2.1.1.2	Name of the Marketing Authorisation holder	Servier Farma B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	Comparator
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	Metformin
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Metformin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Cimetidine
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Cimetidine
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

patients with mCRC with an indication for lonsurf treatment.

patiënten met gemetastaseerd colorectaalcarcinoom met een indicatie voor behandeling middels Lonsurf.

E.1.1.1

Medical condition in easily understood language

patients with metastatic bowel cancer

patiënten met uitgezaaide darmkanker

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

1. To determine the possible drug interaction between Lonsurf and metformin on Lonsurf plasma pharmacokinetics (AUC) in patients with metastatic colorectal cancer.
2. To determine the possible interaction between Lonsurf and cimetidine on Lonsurf plasma pharmacokinetics (AUC) in patients with metastatic colorectal cancer. of concomitant administration of Lonsurf with metformin and cimetidine on Lonsurf and metformin exposure.

1. de mogelijke drug-drug interactie bepalen tussen lonsurf en metformine d.m.v. het bepalen van de lonsurf plasma area under the curve (AUC) in patiënten met gemetastaseerd colorectaalcarcinoom
2. de mogelijke drug-drug interactie bepalen tussen lonsurf en cimetidine d.m.v. het bepalen van de lonsurf plasma area under the curve (AUC) in patiënten met gemetastaseerd colorectaalcarcinoom

E.2.2

Secondary objectives of the trial

1. To determine the possible drug interaction between Lonsurf and metformine on metformin plasma trough concentration in patients with metastatic colorectal cancer.
2. Other pharmacokinetic outcomes of both Lonsurf and metformine (i.e. clearance, maximum concentration (Cmax) and time until maximum concentration (tmax)).
3. To evaluate the incidence and severity of side-effects of treatment with Lonsurf in absence and presence of metformin and cimetidine.

1. bepalen van de invloed van lonsurf op de concentratie (dalspiegel) van metformine
2. Invloed van gelijktijdige toedienen van lonsurf i.c.m. metformine of cimetidine op andere farmacokinetische parameters naast de AUC (klaring, maximale concentratie (Cmax) en tijd tot Cmax (tmax)).
3. de incidentie en ernst van de bijwerkingen van lonsurf bepalen in aan- en afwezigheid van metformine en cimetidine.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years
2. Patients with a confirmed diagnosis of metastatic colorectal cancer with an indication for Lonsurf treatment.
3. WHO performance ≤ 1
4. Able and willing to sign the Informed Consent Form prior to screening evaluations
5. No concurrent medication or supplements which can interact with either Lonsurf, metformin or cimetidine during the study period (e.g. strong OCT2 or MATE1 inhibitors).
6. Abstain from grapefruit, grapefruit juice, herbal dietary supplements, acidic beverages (e.g. Cola) and herbal tea during the study period
7. Adequate baseline patient characteristics (complete blood count, serum biochemistry which involves sodium, potassium, creatinine, calculation of creatinine clearance, AST, ALT, gamma glutamyltranspeptidase, lactate dehydrogenase, ALP, Total bilirubin, Albumin, glucose)
8. BMI 18-30 kg/m2
9. Patients being treated with Lonsurf for any other indication, e.g. as part of experimental treatment in a clinical trial, are also allowed to participate in this trial.

1. Leeftijd ≥ 18 jaar
2. Patiënten met een diagnose van gemetastaseerd colorectaal carcinoom met een indicatie voor behandeling middels Lonsurf
3. WHO perfomance status ≤ 1
4. Getekende Informed Consent
5. Geen medicatie of supplementen welke klinische relevante interacties kunnen geven met Lonsurf, Metformine of cimetidine tijdens de studie. (o.a. sterke OCT2 of MATE1 inhibitors)
6. bereid om af te zien van het gebruik van grapefruit, voedingssupplementen, zure dranken als cola en kruidenthee tijdens de studie periode
7. Adequate baseline karakteristieken (compleet bloedbeeld, serum biochemie met natrium, kalium, kreatinine, GFR, ASAT, ALAT, Gamma GT, LDH, bilirubine, albumine, glucose)
8. BMI 18-30 kg/m2
9. Patienten die behandeld worden met Lonsurf voor elke andere indicatie, b.v. als onderdeel van een experimentele behandeling in een klinische trial, worden ook toegestaan om deel te nemen aan deze trial.

E.4

Principal exclusion criteria

1. Pregnant or lactating patients
2. Patients with known impaired drug absorption (e.g. gastrectomy and achlorhydria)
3. Known serious illness or medical unstable conditions that could interfere with this study requiring treatment (e.g. HIV, hepatitis, Varicella zoster or herpes zoster, organ transplants, kidney failure (GFR<30), serious liver disease (e.g. severe cirrhosis), cardiac and respiratory diseases)
4. Patient with diabetes mellitus type 2 using metformine as standard of care

1. zwangere patiënten of borstvoeding gevende patiënten
2. patienten met bekende verminderde absorptie van medicatie (bv. bij gastrectomie)
3. bekende serieuze ziekte of medisch onstabiele condities die kunnen interfereren met de studie behandeling (bijvoorbeeld HIV, varicella zoster of herpes zoster, orgaantransplantaties, nierfalen (GFR<30), gevorderd leverfalen (b.v. ernstige cirrose), hart- en longziekten)
4. patienten met diabetes mellitus type 2, die metformine gebruiken als standard of care

E.5 End points

E.5.1

Primary end point(s)

To determine the influence of concomitant administration of Lonsurf with metformin and cimetidine on Lonsurf and metformin exposure.

Het bepalen van de invloed op blootstelling van lonsurf van metformine en cimetidine en de invloed van lonsurf op de blootstelling van metformine.

E.5.1.1

Timepoint(s) of evaluation of this end point

end of study

einde van de studie

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

end of study

einde van de studie

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

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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.8.5

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

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

last visit last patient

laatste visite laatste patiënt

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	No
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	No
F.2.2	Male	No
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	No
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state

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

2020-03-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-05-11

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