Clinical Trials Register

Summary
EudraCT Number:	2014-002178-35
Sponsor's Protocol Code Number:	DC2014ELIX001
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:	2014-08-05
Trial results	View 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

2014-002178-35

A.3

Full title of the trial

A phase 4, monocenter, randomized, open label, comparator-controlled, parallel-group, mechanistic intervention trial to assess the effect of 8-week treatment with the glucagon-like peptide-1 receptor agonist lixisenatide versus insulin glulisine on renal physiology and biomarkers in insulin glargine-treated patients with type 2 diabetes mellitus

A.3.1

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

The renal effects of lixisenatide (a novel, gut-hormone based diabetes drug) and insulin glulisine (a common, wideley diabetes drug)

Een onderzoek naar de werking van lixisenatide (een nieuw, op darmhormoon gebaseerd diabetes medicijn) en insuline glulisine (een veelgebruikt gangbaar diabetes medicijn) op de nierfunctie

A.3.2

Name or abbreviated title of the trial where available

ELIXIRS: Effect of LIXIsenatide on the Renal System

ELIXIRS: Effect van LIXIsenatide op het Renale Systeem

A.4.1

Sponsor's protocol code number

DC2014ELIX001

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1151-0579

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	VU University Medical Center
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	VU University Medical Center
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Sanofi-Aventis Netherlands 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	VU University Medical Center
B.5.2	Functional name of contact point	Lennart Tonneijck
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117, Room ZH 4A65
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310204440651
B.5.5	Fax number	00310204443349
B.5.6	E-mail	l.tonneijck@vumc.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	Lyxumia
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Groupe
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Lixisenatide
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous 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	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	Lyxumia
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Groupe
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Lixisenatide
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous 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	Apidra
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Deutschland GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Insulin glulisine
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

Type 2 Diabetes Mellitus

Type 2 Diabetes

E.1.1.1

Medical condition in easily understood language

Diabetes

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

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

Primary objective: To assess the long-term effects (i.e. after 8-week drug exposure) of the GLP-1RA lixisenatide versus insulin glulisine on renal hemodynamics (glomerular filtration rate/effective renal plasma flow) in patients with type 2 diabetes

E.2.2

Secondary objectives of the trial

Secondary objectives: renal damage, renal tubular function, blood pressure

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Type 2 diabetes mellitus
•Caucasian
•Both genders (females must be post-menopausal; no menses >1 year)
•Age: 35 - 75 years
•BMI: 25 - 40 kg/m2
•HbA1c: 6.5 - 10% DCCT (48 - 86 mmol/mol International Federation of Clinical Chemistry)
•Stable treatment with basal insulin glargine and metformin or basal insulin glargine alone
•Fasting plasma glucose (FPG) <10 mmol/L or the use of >50 units of basal insulin glargine
•Hypertension should be under control, i.e. <140/90 mmHg, and treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months.
•Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months.
•Written informed consent

E.4

Principal exclusion criteria

•Current/chronic use of the following medication: TZD, SU derivative, GLP-1RA, DPP-4I, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics, will only be excluded when these drugs cannot be stopped for the duration of the study.
•Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing
•Hypoglycemia unawareness based on investigator judgment
•History of severe hypoglycemia that required emergency hospital treatment within 3 months prior to screening
•Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
•Pregnancy
•Current urinary tract infection and active nephritis
•Recent (<6 months) history of cardiovascular disease, including:
oAcute coronary syndrome
oChronic heart failure (New York Heart Association grade II-IV)
oStroke or transient ischemic neurologic disorder
•Current atrial fibrillation
•Complaints compatible with or established gastroparesis, neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
•Active liver disease or a 3-fold elevation of liver enzymes (aspartate aminotransferase (AST)/alanine aminotransferase (ALT)) at screening
•History of or actual pancreatic disease
•History of or actual malignancy
•History of or actual severe mental disease
•Substance abuse (alcohol: defined as >4 units/day)
•Allergy to any of the agents used in the study (i.e. GLP-1RA, inulin, metacresol (component lixisenatide and insulin glulisine), PAH, latex (component of PAH vial stopper))
•Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
•Inability to understand the study protocol or give informed consent

E.5 End points

E.5.1

Primary end point(s)

To assess changes from baseline following 8-week treatment with a GLP-1RA versus a single dose of insulin on renal hemodynamics measured as:
•Glomerular filtration rate (measured by the inulin-clearance technique)
•Effective renal plasma flow (measured by the para-aminohippurate acid clearance technique)

E.5.1.1

Timepoint(s) of evaluation of this end point

Renal hemodynamics are assessed at baseline and after 8 weeks of treatment

E.5.2

Secondary end point(s)

To assess changes from baseline following 8-week treatment with a GLP-1RA versus a single dose of insulin on:
•Renal damage, measured by urine biomarkers as:
oUrinary albumin excretion (Glomerular)
oNeutrophil gelatinase-associated lipocalin and Kidney injury molecule-1 (Tubular)
•Renal tubular function, measured as:
oFractional sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate- and urea excretion
oUrine osmolality
•Systolic blood pressure, diastolic blood pressure and mean arterial pressure (measured by oscillometric blood pressure device)

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints are assessed at baseline and after 8 weeks 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

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

Yes

E.6.13.1

Other scope of the trial description

Mechanistic: the aim is to assess changes in renal physiology using a GLP-1RA versus an insulin analog

Mechanistisch: het doel is om veranderingen te bepalen in renale fysiologie tussen een GLP-1RA versus een insuline analoog

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

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.8.5

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

LVLS

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

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:

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

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

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

No different treatment is expected after completion of the study. Participants will return to their own physician.

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

2014-08-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-08-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-08-14

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