Clinical Trials Register

Summary
EudraCT Number:	2008-000976-26
Sponsor's Protocol Code Number:	CV181-066
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-07-21
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2008-000976-26

A.3

Full title of the trial

A 4-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial to Evaluate The Efficacy and Safety of Saxagliptin in Comparison to Placebo as Add-on Treatment to Metformin XR in Subjects with Type 2 Diabetes who have Inadequate Glycemic Control with Diet and Exercise and a Stable Dose of Metformin XR ≥ 1500 mg/day

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

CV181-066

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	BRISTOL-M.SQUIBB
B.1.3.4	Country	Italy
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	No
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	saxagliptin
D.3.2	Product code	BMS-477118-11
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	saxagliptin
D.3.9.1	CAS number	361443-04-8
D.3.9.2	Current sponsor code	BMS-477118-11
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	5
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	glucophage
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Information not present in EudraCT
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	Metformin
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	2000
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Film-coated 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

Type II diabetes

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10063624
E.1.2	Term	Type II diabetes mellitus inadequate control

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 compare after 4 weeks of oral administration of double-blind treatment, the change from baseline in 24-hour mean weighted glucose achieved with saxagliptin 5 mg versus placebo as add on treatment to a stable dose of metformin XR ≥ 1500 mg/day

E.2.2

Secondary objectives of the trial

1) Change from baseline to Week 4 (Day 28) in 4-hour mean weighted postprandial glucose (after the evening meal). 2) Change from baseline to Week 4 (Day 28) in 2-hour postprandial plasma glucose (PPG, 2-hour after the evening meal). 3) Change from baseline to Week 4 (Day 28) in mean daily glucose (calculated as 7 daily, finger stick glucose measurements (pre-meal, 2-hour post-meal and at bedtime). Mean daily glucose will be calculated based on finger stick glucose measurements collected by the subjects at home in a 3-day period, prior to collection of the 24-h blood samples. 4) Change from baseline to Week 4 (Day 28) in fasting plasma glucose (FPG

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed Written Informed Consent a) Subjects must be willing and able to give written informed consent. 2) Target Population a) Subjects with a diagnosis of type 2 diabetes mellitus requiring treatment with at least 1500 mg, but not greater than 2550 mg of a stable dose of metformin IR or XR as monotherapy for at least 8 weeks prior to screening are eligible b) A1C ≥ 7% and ≤ 10% obtained at the screening visit. c) Fasting C-peptide concentration ≥ 1.0 ng/ml at the screening visit. d) Body mass index ≤ 40 kg/m2 at the screening visit. 3) Age and Sex a) Men and women, ages 18 to 77 years of age. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized

E.4

Principal exclusion criteria

1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study and for up to 4 weeks after the last dose of investigational product. b) WOCBP using a prohibited contraceptive method. c) Women who are pregnant or breastfeeding. d) Women with a positive pregnancy test on enrollment or prior to investigational product administration. 2) Target Disease Exceptions a) Symptoms of poorly controlled diabetes that would preclude participation in this placebo-controlled trial including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the last three months prior to screening or other signs and symptoms. b) History of diabetic ketoacidosis or hyperosmolar nonketotic coma. c) Insulin therapy within one year of screening (with the exception of insulin therapy during a hospitalization or use in gestational diabetes. 3) Medical History and Concurrent Diseases a) Significant cardiovascular history defined as: i) History of myocardial infarction, coronary angioplasty or bypass graft(s), valvular disease or repair, unstable angina pectoris, transient ischemic attack, or cerebrovascular accidents within six months prior to study entry. ii) Congestive heart failure defined as New York Heart Association (NYHA) stage III and IV and/or known left ventricular ejection fraction of ≤ 40%. b) Chronic or repeated intermittent corticosteroid treatment (subjects receiving stable doses of replacement corticosteroid therapy may be enrolled). c) History of unstable or rapidly progressing renal disease. d) History of alcohol or drug abuse within the previous one year. e) Unstable major psychiatric disorders. f) Immunocompromised individuals such as subjects who have undergone organ transplantation or subjects diagnosed with human immunodeficiency virus. g) History of hemoglobinopathies (sickle cell anemia or thalassemias, sideroblastic anemia). h) Donation of blood or plasma to a blood bank within three months of screening. i) Administration of any other investigational drug or participation in a clinical research trial within 30 days of planned enrollment to this study. j) Any condition which in the Investigator’s opinion may render the subject unable to complete the study or which may pose significant risk to the subject. 4) Physical and Laboratory Test Findings a) Active liver disease and/or significant abnormal liver function defined as AST > 2 x ULN and/or ALT > 2x ULN and /or serum total bilirubin > 2.0 mg/dl. b) History of positive serologic evidence of current infectious liver disease including anti-HAV (IgM), HbsAg, or anti-HCV. Subjects who may have isolated positive anti HBs may be included. c) Serum creatinine (Scr) ≥ 1.5 mg/dl (132.6 μmol/L) for males and ≥ 1.4 mg/dl (123.8 μmol/L) for females. d) Creatine Kinase ≥ 3x ULN. e) Anemia, of any etiology defined as hemoglobin ≤ 12.0 g/dL (120 g/L) for men and hemoglobin ≤ 11.0 g/dL (110 g/L) for women. f) Subjects who have an abnormal TSH value at screening will be further evaluated by free T4. Subjects with an abnormal free T4 will be excluded. 5) Allergies and Adverse Drug Reactions a) Subjects who have contraindications to therapy as outlined in the Saxagliptin Investigator Brochure, metformin XR/metformin package insert package insert. 6) Prohibited Therapies and/or Medications 7) Other Exclusion Criteria

E.5 End points

E.5.1

Primary end point(s)

la variabile primaria di efficacia e' la variazione della glicemia media ponderata delle 24 ore (MWG) dal basale alla Settimana 4

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

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

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

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.1.3	Elderly (>=65 years)	Yes
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	26
F.4.2	For a multinational trial
F.4.2.1	In the EEA	116
F.4.2.2	In the whole clinical trial	220

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

2008-08-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-07-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2009-02-27

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