Clinical Trials Register

Summary
EudraCT Number:	2011-006118-15
Sponsor's Protocol Code Number:	CLAF237ADE07
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:	2012-03-28
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

2011-006118-15

A.3

Full title of the trial

Multicentric cross-over trial to assess the glycemic profiles on 8 weeks of vildagliptin and sitagliptin treatment, each, in type-2 diabetic patients with a pre-existing cardiovascular disease pre-treated with insulin, using a PROBE-design

A.3.1

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

Comparison of the glycemic profiles of vildagliptin and sitagliptin treatment in type-2 diabetic patients

A.3.2

Name or abbreviated title of the trial where available

CGM-visit

A.4.1

Sponsor's protocol code number

CLAF237ADE07

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	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	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	Januvia
D.2.1.1.2	Name of the Marketing Authorisation holder	MSD Sharp & Dohme Ltd.
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	Film-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.3.9.1	CAS number	654671-77-9
D.3.9.3	Other descriptive name	SITAGLIPTIN PHOSPHATE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB25198
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.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 with pre-existing cardiovascular disease

E.1.1.1

Medical condition in easily understood language

type-2 diabetes mellitus with pre-existing cardiovascular disease

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	14.1
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

To demonstrate that vildagliptin leads to a favorable hypoglycemic profile compared to sitagliptin, after 8 weeks of treatment, each, when used in combination with insulin. The hypoglycemic profile will be defined as the area under the glucose-time profile obtained by a 5 day-continuous glucose monitoring where the glucose levels are lower than the hypoglycemia threshold of 70 mg/dL.

E.2.2

Secondary objectives of the trial

1. To evaluate whether vildagliptin leads to a lower number of hypoglycemic events. compared to sitagliptin, when used in combination with insulin.
2. To evaluate by CGM measurement whether vildagliptin leads to a shorter mean duration of hypoglycemic events compared to sitagliptin, when used in combination with insulin.
3. To evaluate by CGM measurement the grade of severity of hypoglycemia measured as the mean amplitude.
4. To evaluate whether vildagliptin leads to a lower number of severe hypoglycemic events compared to sitagliptin, when used in combination with insulin.
5. To evaluate whether vildagliptin leads to less glucose fluctuations during the day.
6. To evaluate if hypoglycemic events increases the risk of ECG abnormalities
7. To evaluate whether treatment with vildagliptin results in lower levels of pro-inflammatory biomarkers (hsCRP, IL-6).
8. To evaluate whether treatment with vildagliptin results in lower pro-insulin/C-Peptide ratio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent must be obtained before any assessment is performed.
2. Ability to comply with all study requirements.
3. Patients with Type 2 diabetes treated with stable, once or twice daily doses (minimal dose of 0.3 unit/kg/day) of basal long-acting or intermediate-acting insulin alone or in pre-mixed combination with rapid-acting or short-acting insulin for at least 12 weeks prior to Visit 1. Stable is defined as ±10% of the Visit 1 dose during the previous 12 weeks.
4. Patients receiving metformin must be on a stable dose of metformin (at least 1500 mg
daily or a maximally tolerated dose) for at least 12 weeks prior to Visit 1.
5. HbA1c ≥7.5 to ≤ 9,0% at Visit 1
6. Known CV disease based on a documented history of one or more of the following at screening:

o Acute coronary syndrome or MI (at least 6 months before V1)
o Stroke/TIA (at least 6 months before V1)
o PCI/CABG (at least 6 months before V1)
o Heart failure NYHA I/II
o Coronary heart disease, diagnosis by coronarogram
o >75% Stenosis of the internal carotid artery, diagnosed by Doppler sonography
o Peripheral arterial disease (Fontaine stage 2)

7. Age: ≥40 to ≤80 years at Visit 1

E.4

Principal exclusion criteria

1. FPG ≥ 270 mg/dL (15 mmol/L) at Visit 1.
2. Use of any of the following medications as assessed at Visit 1:
a. rapid or short acting insulin except in pre-mixed formulations with intermediate or long-acting insulin; insulin administration more frequently than twice-daily, or total insulin dose < 0.3 unit/kg/day for the past 12 weeks
b. use of any oral antidiabetic medication or GLP-1 analogues within the last 12 weeks, except metformin
c. use of weight control products including weight-loss medications in the last 12 weeks.
d. use of oral (≥7 consecutive days) or chronic parenteral or intra-articular corticosteroid treatment within the last 8 weeks. Inhaled or topical steroids without systemic effects will be allowed.
e. treatment with growth hormone within the previous 6 months.
f. treatment with any drug of known and frequent toxicity to a major organ, or that may interfere with the interpretation of the efficacy and safety data during the study.
3. a history or evidence of any of the following at Visit 1:
a. acute metabolic conditions such a ketoacidosis, lactic acidosis or hyperosmolar state (including precoma and 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 6 months.
g. sustained and clinically relevant ventricular arrhythmia (patients with premature ventricular contractions if deemed not clinically significant may be enrolled).
h. Patients with permanent atrial fibrillation or pacemaker.
i. active substance abuse, alcohol abuse and history of alcohol-related diseases within the past 2 years.
j. type 1 diabetes, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes (e.g. Cushing’s syndrome or acromegaly-associated diabetes).
k. malignancy of an organ system
l. hepatic disorder
m. acute infections which may affect blood glucose control within the past 4 weeks.
4. significant laboratory abnormalities
5. electrocardiographic abnormalities
6. previous or current participation in any vildagliptin clinical study (except CLAF237A23135 [vildagliptin add-on-insulin trial]).
7. concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
8. donation of blood or significant blood loss equaling to at least one unit of blood (500 mL) within the past 2 weeks before screening or a blood transfusion within the past 12 weeks before screening or planned regular transfusions during the study period.
9. potentially unreliable, inability to comply with the study procedures or medications, and/or judged by the investigator to be unsuitable for the study.
10. use of an investigative drug within 30 days or 5 half-lives of the drug before screening, whichever is longer.
11. Known sensitivity to study drug(s) or class of study drug(s)
12. Allergies or intolerance against test meal components; vegetarians.
13. Patients with severe medical condition(s) that in the view of the investigator prohibits participation in the study
14. Study personnel or first degree relatives of investigator(s) must not be included in the study.
15. Women
o who are pregnant or breast feeding
o who are menstruating and capable of becoming pregnant

E.5 End points

E.5.1

Primary end point(s)

The primary variable is the hypoglycemia profile computed as the area under the glucose-time profile where the glucose levels are lower than the hypoglycemia threshold of 70 mg/dl. This area seems to be a sensitive measure to summarize the frequency, the severity and the duration of hypoglycemia. The area will be computed from the data of the CGMS iPro2 Continuous Glucose Recorder collected during 5 days.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 8 weeks of treatment

E.5.2

Secondary end point(s)

The number of (severe) hypoglycemic events will be compared between treatment groups using a negative binomial regression model with factors patient and treatment. Rate ratios and their confidence intervals will be computed. The duration of hypoglycemia and the glucose fluctuations (MAGE) will be analyzed analogously to the primary endpoint using ANOVA. For calculating MAGE the average interstitial glucose level and its standard deviation (SD) measured at visits 2.3, 3.3 and 5.3 will be calculated from all of the available glucose measurements made during CGM. The mean amplitude of glycemic excursion over 24 hours (MAGE) was designed to quantify major excursions of glycemia but exclude minor oscillations. Therefore only changes greater than 1 SD of average interstitial glucose level will be included in the calculation. MAGE will be calculated as the arithmetic mean of all differences between consecutive peaks and valleys or valley – peak direction (Service et al., 1070). Peaks (valleys) are defined as interstitial glucose values preceded and followed by an increase (decrease) and decrease (increase), respectively.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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)

Yes

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

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

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:	25
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	25
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	50

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

2012-06-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-09-08

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