Clinical Trials Register

Summary
EudraCT Number:	2015-004224-59
Sponsor's Protocol Code Number:	MK-0431-848
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-04-27
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

Czechia - SUKL

A.2

EudraCT number

2015-004224-59

A.3

Full title of the trial

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Sitagliptin During Metformin Up-titration Compared with Metformin Up-titration Alone in Subjects with Type 2 Diabetes Mellitus

Multicentrické, dvojitě zaslepené, placebem kontrolované klinické hodnocení fáze III, jehož cílem je zkoumat bezpečnost a účinnost přídatné léčby sitagliptinem při zvyšování dávek metforminu ve srovnání se samotným zvyšováním dávek metforminu u subjektů s diabetes mellitus II. typu

A.3.1

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

Sitagliptin add-on to Metformin up-titration Study

Studie přídatné léčby sitagliptinem při zvyšování dávek metforminu

A.3.2

Name or abbreviated title of the trial where available

Sitagliptin Addition during Metformin Up-titration

Přídatná léčba sitagliptinem při zvyšování dávek metforminu

A.4.1

Sponsor's protocol code number

MK-0431-848

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	Merck Sharp & Dohme Corp.
B.1.3.4	Country	United States
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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme Corp.
B.5.2	Functional name of contact point	Global Clinical Trial Operations
B.5.3	Address:
B.5.3.1	Street Address	One Merck Drive, P.O. Box 100
B.5.3.2	Town/ city	Whitehouse Station, New Jersey
B.5.3.3	Post code	08889-0100
B.5.3.4	Country	United States
B.5.4	Telephone number	+001267-305-1263

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	JANUVIA
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
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.3.2	Product code	MK-0431
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.3.8	INN - Proposed INN	SITAGLIPTIN PHOSPHATE
D.3.9.1	CAS number	654671-78-0
D.3.9.3	Other descriptive name	SITAGLIPTIN PHOSPHATE
D.3.9.4	EV Substance Code	SUB25200
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
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 2 Diabetes mellitus

E.1.1.1

Medical condition in easily understood language

Type 2 Diabetes mellitus

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

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

1. To assess the effect of up-titration of metformin plus the addition of sitagliptin compared with the up-titration of metformin alone on reduction from baseline in A1C.
2. To assess the overall safety and tolerability of up-titration of metformin plus the addition of sitagliptin compared to up-titration of metformin alone.

E.2.2

Secondary objectives of the trial

1. To assess the overall safety and tolerability of up-titration of metformin plus the addition of sitagliptin compared to up-titration of metformin alone.
2. To assess the effect of up-titration of metformin plus the addition of sitagliptin compared to up-titration of metformin alone on reduction from baseline in fasting plasma glucose.
3. To assess the proportion of subjects with baseline A1C ≥ 8.5% that are at the A1C goal of <7% (<53 mmol/mol) with up-titration of metformin plus the addition of sitagliptin compared with the up-titration of metformin alone.
4. To assess the proportion of subjects receiving glycemic rescue therapy with up-titration of metformin plus the addition of sitagliptin compared with the up -titration of metformin alone.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.

E.3

Principal inclusion criteria

At Visit 1/Screening
1. Have T2DM and be ≥18 years of age
2. Be on one of the following treatment regimens:
- Be on stable Met-IR monotherapy 1000 mg/day for ≥8 weeks with a Visit 1/Screening A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).
OR
– Be on stable Met-XR monotherapy 1000 mg/day for ≥8 weeks with a Visit 1/Screening A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).
OR
– Not on any AHA for ≥8 weeks (≥12 weeks if previously taking thiazolidinediones) with a Visit 1/Screening A1C ≥8.5% and ≤12.0% (≥69 mmol/mol and ≤108 mmol/mol).
OR
– Be on stable monotherapy with a sulfonylurea, a glinide, or an α-glucosidase inhibitor for ≥8 weeks with a Visit 1/Screening A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).
3. Have a body mass index (BMI) ≥18.0 kg/m2.
At Visit 3
4. Be on stable Met-IR monotherapy 1000 mg/day as described in Section 2.1, Table 1 with a Visit 3 /Week -2 A1C of ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol)
At Visit 4/Day 1
5. Be ≥80% compliant with the placebo run-in medication (as determined by subject report)

E.4

Principal exclusion criteria

At Visit 1/Screening
1. Has a history of type 1 diabetes mellitus or a history of ketoacidosis or subject is assessed by the investigator as possibly having type 1 diabetes mellitus confirmed with a C-peptide <0.7 ng/mL (0.23 nmol/L) or has a history of secondary causes of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant).
2. Has a known hypersensitivity or intolerance to any DPP-4 inhibitor.
3. Has a known hypersensitivity or intolerance to metformin.
At Visit 1/Screening (cont.)
4. Has been treated with any of the following agents within 8 weeks (12 weeks for thiazolidinediones) of Visit 1/Screening:
– Insulin of any type (except for short-term use [i.e., ≤7 days] during concomitant illness or other stress)
– Dipeptidyl-peptidase 4 inhibitors (DPP-4 inhibitor)
– Pioglitazone or rosiglitazone (thiazolidinediones)
– GLP-1R agonists
– SGLT2 inhibitors
– Bromocriptine (Cycloset™)
– Colesevelam (Welchol™)
– Any other AHA with the exception of protocol-approved agents
At Visit 1/Screening (cont.)
5. Exclusion Criteria Based on Laboratory Abnormalities:
eGFR:<60 mL/min/1.73 m2, ALT or AST: >2 times Upper Limit of Normal (ULN)
TSH: Outside central laboratory normal range Hemoglobin: male: <11 g/dL (110 g/L)
female: <10 g/dL (100 g/L)
Triglycerides: >600 mg/dL (6.78 mmol/L)
At Visit 3/Week -2
6. Has a clinically significant ECG finding that requires further diagnostic evaluation or intervention
7. Has an FPG consistently (i.e., measurement repeated and confirmed within 7 days) >270 mg/dL (15.0 mmol/L).
8. Has a fasting TG level >600 mg/dL (6.8 mmol/L).
At Visit 4/Randomization/Day 1
9. Has a site fasting fingerstick glucose (FFSG) of <120 mg/dL (6.7 mmol/L) or >270 mg/dL (15.0 mmol/ L).
10. Blood pressure and lipid medication are not at a stable dose for at least 4 weeks.

E.5 End points

E.5.1

Primary end point(s)

A1C – change from baseline at Week 20

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 20

E.5.2

Secondary end point(s)

Proportion of subjects with A1C <7.0% at Week 20
Fasting Plasma Glucose (FPG) – change from baseline at Week 20

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 20

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

Yes

E.6.11

Pharmacogenomic

Yes

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.8.2.4

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

Information not present in EudraCT

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

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

Argentina

Brazil

Canada

Czech Republic

Guatemala

Mexico

Russian Federation

United States

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

380

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

380

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)

None

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

2016-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-02-01

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