Clinical Trials Register

Summary
EudraCT Number:	2007-002218-21
Sponsor's Protocol Code Number:	MK0431-068
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:	2007-12-10
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

2007-002218-21

A.3

Full title of the trial

A Phase III Randomized, Active-Comparator (Pioglitazone) Controlled Clinical Trial to
Study the Efficacy and Safety of Sitagliptin and MK-0431A (A Fixed-Dose Combination
Tablet of Sitagliptin and Metformin) in Patients With Type 2 Diabetes Mellitus

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

MK0431-068

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	MERCK SHARP DOHME
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	metformina e sitagliptin
D.3.2	Product code	MK0431A
D.3.4	Pharmaceutical form	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.3.9.2	Current sponsor code	MK0431A
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)	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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
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	Information not present in EudraCT
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	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	Pioglitazone
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	15
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	Information not present in EudraCT
D.3.11.8	Extractive medicinal product	Information not present in EudraCT
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients With Type 2 Diabetes Mellitus

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	6.1
E.1.2	Level	PT
E.1.2	Classification code	10049746

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) Objective: To assess the effect of the fixed-dose combination sitagliptin/metformin
(MK-0431A) 50/1000 mg b.i.d. compared with the effect of pioglitazone 45 mg q.d.
on HbA1c at Week 40.
Hypothesis: The fixed-dose combination sitagliptin/metformin (MK-0431A)
50/1000 mg b.i.d. will lower HbA1c (mean change from baseline) more than
pioglitazone 45 mg q.d. at Week 40.
(2) Objective: After 12 weeks, to assess the HbA1c-lowering efficacy of treatment with
sitagliptin.
Hypothesis: After 12 weeks of treatment, sitagliptin results in a significant reduction
of HbA1c from baseline.
(3) Objective: To assess the safety and tolerability of sitagliptin and the fixed-dose
combination sitagliptin/metformin (MK-0431A).
Hypothesis: Sitagliptin and the fixed-dose combination sitagliptin/metformin
(MK-0431A) are well-tolerated.

E.2.2

Secondary objectives of the trial

(1) Objective: To assess the effect of the fixed-dose combination sitagliptin/metformin
(MK-0431A) 50/1000 mg b.i.d. compared with the effect of pioglitazone 45 mg q.d.
on the proportion of patients achieving glycemic goals (HbA1c <7.0%, <6.5%) at
Week 40.
Hypothesis: The fixed-dose combination sitagliptin/metformin (MK-0431A)
50/1000 mg b.i.d. will result in a higher proportion of patients who achieve the
glycemic goal of HbA1c <7.0% than pioglitazone 45 mg q.d. at Week 40.
(2) Objective: To assess the effect of the fixed-dose combination sitagliptin/metformin
(MK-0431A) 50/1000 mg b.i.d. compared with the effect of pioglitazone 45 mg q.d.
on 2-hour post prandial glucose (PPG) as determined by MTT at Week 40.
Hypothesis: The fixed-dose combination of sitagliptin/metformin (MK-0431A)
50/1000 mg b.i.d. will result in a greater reduction of the 2-hour PPG after standard
meal challenge from baseline than pioglitazone 45 mg q.d. at Week 40.

E.2.3

Trial contains a sub-study

Information not present in EudraCT

E.3

Principal inclusion criteria

At Visit 1
a. Patient has T2DM.
b. Patient is ≥18 and ≤78 years of age on day of signing informed consent.
c. Patient has an HbA1c of 7.5% and ≤12% at Visit 1.
d. Patient is drug-naïve (off antihyperglycemic agent [AHA] therapy for at least
3 months prior to the Screening Visit/Visit 1, and no more than 4 weeks cumulative
AHA therapy over the previous 3 years).
e. Patient is a male, or a female who is unlikely to conceive, as indicated by at least one
“yes” answer to the following questions:
1) Patient is a male.
2) Patient is a surgically sterilized female.
3) Patient is a postmenopausal female ≥45 years of age with >2 years since last
menses.
4) Patient is a non-sterilized, premenopausal female and agrees to abstain from
heterosexual activity or to use an adequate method of contraception:
Note: Acceptable methods of birth control are: hormonal contraceptive,
intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge,
condom, or vasectomy.
f. Patient understands the study procedures, alternative treatments available, and risks
involved with the study and voluntarily agrees to participate by giving informed
written consent.
At Visit 3/Day 1/Randomization
Patient has ≥85% compliance with placebo treatment during the single-blind run-in as
measured by site performed tablet count.

E.4

Principal exclusion criteria

At Visit 1
Glucose Metabolism and Therapy Criteria
a. Patient has a history of type 1 diabetes mellitus or a history of Ketoacidosis.
OR
Patient is assessed by the investigator as possibly having type 1 diabetes confirmed
with a C-peptide <0.7 ng/mL (0.23 nmol/L). Note: Only patients assessed by the
investigator as possibly having type 1 diabetes should have C-peptide measured at
Visit 1.
b. Patient has symptomatic hyperglycemia requiring immediate initiation of
antihyperglycemic therapy.
Patients Requiring Specific Treatments
c. Hypersensitivity or contraindication to biguanide medication (i.e., metformin),
pioglitazone hydrochloride (i.e., ACTOS™), or thiazolidinedione medication.
d. Patient is on a weight loss program and is not in the maintenance phase, or patient
started on a weight loss medication (e.g., orlistat, sibutramine, or rimonabant) within
8 weeks of Visit 1.
e. Patient has received treatment with an investigational drug within the prior 3 months
or is otherwise participating in another clinical trial.
f. Patient has previously been treated clinically with sitagliptin, vildagliptin, or
exenatide or has previously been in clinical study with any DPP-4 inhibitor or
incretin mimetic.
g. Patient is on lipid-modifying medications (or requires initiation of lipid-modifying
medications) and will not be on a stable dose for at least 4 weeks prior to Visit 3.
h. Patient is on or likely to require treatment with immunosuppressive/
immunomodulating agents (e.g., cyclosporine, methotrexate, etanercept) or patient
is on or likely to require treatment ≥14 consecutive days or repeated courses of
pharmacologic doses of corticosteroids.
Note: inhaled, nasal, and topical corticosteroids are permitted.
i. Patient is on or likely to require treatment with CYP2C8 inhibitors (such as
gemfibrozil) or CYP2C8 inducers (such as rifampicin).
j. Patient has undergone surgery within 30 days prior to Visit 1 or has planned major
surgery.
Note: Patients who have undergone minor surgery within the prior 30 days or have
planned minor surgery may be enrolled upon approval by the Merck Medical
Monitor.

E.5 End points

E.5.1

Primary end point(s)

To assess the effect of the fixed-dose combination sitagliptin/metformin
(MK-0431A) 50/1000 mg b.i.d. compared with the effect of pioglitazone 45 mg q.d.
on HbA1c at Week 40.

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

Information not present in EudraCT

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Information not present in EudraCT

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)

Yes

E.8.2.2

Placebo

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.8.5

The trial involves multiple Member States

Yes

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

Information not present in EudraCT

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	Information not present in EudraCT
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Information not present in EudraCT
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	36
F.4.2	For a multinational trial
F.4.2.1	In the EEA	178
F.4.2.2	In the whole clinical trial	498

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

2007-11-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-12-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-01-16

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