Clinical Trials Register

Summary
EudraCT Number:	2012-001143-46
Sponsor's Protocol Code Number:	CLAF237ADE08
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-04-27
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

Germany - BfArM

A.2

EudraCT number

2012-001143-46

A.3

Full title of the trial

A randomized open-label study to compare safety and efficacy of vildagliptin versus NPH insulin add-on to glimepiride in patients with type 2 diabetes mellitus that do not reach adequate glycemic control on their current sulfonylurea monotherapy

A.3.1

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

Comparison of safety and efficacy of vildagliptin versus NPH insulin add-on to glimepiride in patients with type 2 diabetes mellitus

A.4.1

Sponsor's protocol code number

CLAF237ADE08

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	Novartis Pharma GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice
B.5.3	Address:
B.5.3.1	Street Address	Roonstr. 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+491802232300
B.5.5	Fax number	+4991127312160
B.5.6	E-mail	infoservice.novartis@novartis.com

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	Galvus
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Vildagliptin
D.3.2	Product code	LAF237
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VILDAGLIPTIN
D.3.9.1	CAS number	274901-16-5
D.3.9.2	Current sponsor code	LAF237
D.3.9.4	EV Substance Code	SUB25199
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	50
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	No
D.2.1.1.1	Trade name	Protaphane FlexPen
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk A/S
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.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	11061-68-0
D.3.9.3	Other descriptive name	INSULIN LONG-ACTING
D.3.9.4	EV Substance Code	SUB25175
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
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	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	Yes
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 that do not reach adequate glycemic control on their current sulfonylurea monotherapy

E.1.1.1

Medical condition in easily understood language

type-2 diabetes mellitus that do not reach adequate glycemic control on their current sulfonylurea monotherapy

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10045242
E.1.2	Term	Type II diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

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 demonstrate that add-on to glimeperide vildagliptin is superior to NPH insulin with respect to the incidence of the combined endpoint, defined as a blood glucose target (HbA1c below 7.0%) without any confirmed hypoglycemic events (BG measurement < 3.9mM (71mg/dL)) and weight gain (+3%) in T2DM patients.
2. To demonstrate that add-on to glimepiride vildagliptin is superior to NPH insulin with respect to the rate of of confirmed hypoglycemic events (BG measurement < 3.9mM (71mg/dL)) in T2DM patients.

E.2.2

Secondary objectives of the trial

• To evaluate the incidence of severe hypoglycemic events in patients treated with vildagliptin versus NPH insulin add-on to glimepiride.
• To evaluate the incidence of symptomatic hypoglycemic events in patients treated with vildagliptin versus NPH insulin add-on to glimepiride.
• To evaluate the proportion of patients treated with vildagliptin versus NPH insulin add-on to glimepiride who reach their blood glucose target (HbA1c below 7.0%) without any confirmed hypoglycemic events.
• To evaluate body weight changes between Visit 2 and study end in patients treated with vildagliptin versus NPH insulin add-on to glimepiride.
• To evaluate the change in HbA1c, between Visit 2 and study end in patients treated with vildagliptin versus NPH insulin add-on to glimepiride.
• To evaluate treatment satisfaction between Visit 2 and study end in patients treated with vildagliptin versus NPH insulin add-on to glimepiride by using the TSQM-9 questionnaire.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age > 18 and < 85 years
2. Written informed consent must be obtained before any assessment is performed.
3. Confirmed diagnosis of T2DM.
4. Contraindicated or intolerant to take metformin.
5. HbA1c of ≥ 7.0% and ≤ 8.5% as determined by a central laboratory at Visit 1 and judged by the investigator to be inadequately controlled that requires the expansion of the current anti diabetic therapy.
6. Patients treated with any SU for at least the prior 12 weeks including a stable dose of glimepiride of 4mg (or if not tolerated, the maximal tolerated dose up to 4mg) for at least 4 weeks prior to Visit 1.

E.4

Principal exclusion criteria

1. Patients who are taking any other anti-diabetes drug (oral or injection) other than an SU component in the preceding 12 weeks.
2. Use of any prohibited medication as per protocol section 6.6.
3. A history or evidence of any of the following:
a. Acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar state (including diabetic precoma or coma) within the past 6 months.
b. Current diagnosis of congestive heart failure (NYHA III or IV).
c. Myocardial infarction within the past 6 months.
d. Coronary artery bypass surgery or percutaneous coronary intervention within the past 6 months
e. Stroke, transient ischemic attack, or reversible ischemic neurologic deficit within the past 6 months.
f. Unstable angina within the past 3 months.
g. Sustained and clinically relevant ventricular arrhythmia (patients with premature ventricular contractions if deemed not clinically significant may be enrolled).
h. Active substance abuse, alcohol abuse and history of alcohol-related diseases within the past 2 years.
i. Type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes (e.g. Cushing’s syndrome or acromegaly-associated diabetes).
j. Malignancy of an organ system (other than localized basal cell carcinoma of the skin) treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
k. hepatic disorder defined as:
• Acute or chronic liver disease, evidence of hepatitis, cirrhosis or portal hypertension.
• History of imaging abnormalities that suggest liver disease (except hepatic steatosis), such as portal hypertension, capsule scalloping, cirrhosis.
l. Evidence of active pancreatitis within the 1 month prior to baseline assessment
4. Any of the following significant laboratory abnormalities as assessed at Visit 1:
a. Clinically significant renal dysfunction: glomerular filtration rate (GFR) <30mL/min/1.73m2 (via modification of diet in renal disease (MDRD) formula).
b. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3x upper limit of normal (ULN), confirmed by repeat measure within 3 working days.
c. Total bilirubin (except patients with Gilbert`s disease) > 2x ULN, confirmed by repeat measure within 3 working days.
d. Clinically significant laboratory abnormalities which, in the opinion of the investigator, cause the patient to be considered inappropriate for inclusion in the study.
5. Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
6. Patients who do not agree to take the study medication and do not want to follow the procedure as required by the study protocol.
7. Patients taking the SU component for longer than 5 years before Visit 1.
8. BMI < 21 or > 45 kg/m2 at Visit 1.
9. Donation of blood (500ml) or significant blood loss equaling to at least one unit of blood within the past 2 weeks of start of study or a blood transfusion within the past 12 weeks or planned regular transfusions during the study period.
10. Potentially unreliable, inability to comply with the study procedures or medications, and/or judged by the investigator to be unsuitable for the study.
11. Use of an investigative drug within 30 days or 5 half-lives of the drug, whichever is longer.
12. History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures
13. Study personnel or first degree relatives of investigator(s) must not be included in the study.
14. Women
o who are pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml))
o who are menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception (Pearl Index <1**) during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche is required before Randomization.
*definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy
**examples of particularly reliable methods with Pearl Index (PI) <1, according to guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe:
• Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9)
• Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.)
• Contraceptive patch (EVRA®, PI= 0.72 uncorr.; 0.9 corr.)
• Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14)
• Progestin-containing contraceptives (Implanon®, PI=0-0.08)
• Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.)
• Intra-uterine progestine device (Mirena®, PI=0.16)

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

24 weeks

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

Yes

E.6.5

Efficacy

Yes

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)

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

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

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

LPLV

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)	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:	60
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
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	160

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

2012-05-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-10-10

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