Clinical Trials Register

Summary
EudraCT Number:	2013-003356-21
Sponsor's Protocol Code Number:	00/0648-DXM2
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:	2013-08-28
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

2013-003356-21

A.3

Full title of the trial

A phase IIa, dose-finding, double-blind, placebo-controlled, double-dummy,
randomized, eightfold cross-over study to investigate the glucose lowering
effects of dextromethorphan alone or in combination with sitagliptin in
subjects with type 2 diabetes mellitus (T2DM) after an oral glucose tolerance
test

A.3.1

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

A.4.1

Sponsor's protocol code number

00/0648-DXM2

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	Profil Institut für Stoffwechselforschung GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Profil Institut für Stoffwechselforschung 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	Profil Institut für Stoffwechselforschung GmbH
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Hellersbergstr. 9
B.5.3.2	Town/ city	Neuss
B.5.3.3	Post code	41460
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4921314018411
B.5.5	Fax number	+4921314018517
B.5.6	E-mail	regulatory@profil.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	Hustenstiller-ratiopharm® Dextromethorphan
D.2.1.1.2	Name of the Marketing Authorisation holder	ratiopharm GmbH
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	Hustenstiller-ratiopharm® Dextromethorphan
D.3.4	Pharmaceutical form	Capsule, hard
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	Dextromethorphanhydrobromid
D.3.9.1	CAS number	125-69-9
D.3.9.3	Other descriptive name	DEXTROMETHORPHAN HYDROBROMIDE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB27099
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	30
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	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	MSD Sharp & Dohme GmbH
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.3.1	Product name	Januvia®
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
D.3.9.3	Other descriptive name	SITAGLIPTIN
D.3.9.4	EV Substance Code	SUB25227
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
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

Diabetes mellitus

E.1.1.1

Medical condition in easily understood language

Diabetes mellitus

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	16.0
E.1.2	Level	PT
E.1.2	Classification code	10067585
E.1.2	Term	Type 2 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

First primary objective:
to find the lowest dose of DXM that, compared to
placebo, exerts BG lowering effects related to an OGTT

Second primary objective:
to demonstrate whether the administration of DXM
on top of sitagliptin exerts additive BG lowering effects related to an OGTT as
compared to sitagliptin alone and DXM alone.

E.2.2

Secondary objectives of the trial

- To compare other pharmacodynamic (PD) properties (based on glucose, insulin and possibly C-peptide and glucagon measurements) of oral DXM alone or on top of sitagliptin (termed: Investigational Medicinal Product – IMP) before and after starting an OGTT. Comparisons will be made as follows:
- DXM different doses compared with placebo for DXM
- DXM different doses + sitagliptin 100 mg compared with DXM alone corresponding doses
- DXM different doses + sitagliptin 100 mg compared with sitagliptin alone
- effective DXM doses (at least 10% higher effect than placebo) compared to sitagliptin 100 mg
- To compare the pharmacokinetic (PK) exposure to DXM and dextrorphan (DX) following an oral DXM dose for 5h post-dosing
- To assess the safety and tolerability after single oral dosing for DXM alone or in combination with sitagliptin

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated written informed consent obtained before any study-related activities
2. Male subjects with a diagnosis of type 2 diabetes mellitus according to ADA criteria at
least 4 months prior to screening
3. Medical history without major pathology (with the exception of type 2 diabetes)
4. On a stable regimen of metformin monotherapy for at least 3 months
5. Aged between 45 and 70 years of age, both inclusive
6. Body mass index (BMI) between 25 and 35kg/m2, both inclusive
7. HbA1c 6.5 and 8.0%
8. A male subject who is sexually active and not surgically sterilized, must agree to use
adequate contraceptive methods as described in Section 3.3.2.1 from the time of first
study drug administration until the end of the study.
9. Ability and willingness to abstain from grapefruit juice (and all grapefruit containing
products) throughout the study starting 24 hours prior to first study drug administration
and from alcohol, methylxanthine-containing beverages or food (coffee, tea, Coke,
chocolate, “power drinks”), tobacco products and from engaging in strenuous physical
activity from 24 hours prior to each admission until discharge from the unit.

E.4

Principal exclusion criteria

1. Subjects with type 1 diabetes, MODY or secondary forms of diabetes such as due to
pancreatitis
2. History of pancreatitis
3. Current or previous treatment with insulin therapy (except for treatment within a clinical
trial, for surgical procedures or during an acute illness for 1 month and more than 3
months before the first administration of study drug)
4. Treatment with any hypoglycemic medication other than metformin within the three
months prior to screening
5. Mean QTc> 450 msec for male (Bazett formula, mean value of 3 consecutive ECGs)
6. Subjects with any severe medical or surgical history of conditions likely to confound
study assessments or study endpoints, for example but not limited to
haemoglobinopathies, inflammatory bowel disease, cystic fibrosis, bariatric surgery
and/or any surgery shortening the intestine, history of galactose intolerance, lactose- or
glucose-galactose-malabsorption
7. Serious respiratory, serious and/or unstable coronary heart disease (unstable angina,
myocardial infarction within the preceding 6 months), congestive heart failure of New
York Heart Association Class II or worse (slight limitation of physical activity;
comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or
dyspnoea), second/third degree heart block, superior vena cava syndrome, uncontrolled
hypertension, history of congenital QT-syndrome within family, history of stroke (within
the preceding 6 months) or serious peripheral vascular disease as judged by the
investigator
8. Marked diabetic complications: severe autonomic or sensory neuropathy including
gastroparesis; proliferative retinopathy as judged by the investigator
9. Any respiratory disease leading to respiratory insufficiency and/or depression including
but not limited to: asthma bronchiale, chronic obstructive pulmonary disease, as judged by
the investigator
10. Clinically significant vital signs including bradycardia with pulse rate < 50/min
11. Subjects with a history, a suspicion, or a family history of medullary thyroid cancer or a
multiple endocrine neoplasia
12. Clinically significant abnormal haematology, biochemistry, lipids, or urinalysis or
coagulation screening tests, as judged by the Investigator
13. Moderate or severe renal dysfunction defined as a calculated GFR <60ml/min using the
MDRD calculation

E.5 End points

E.5.1

Primary end point(s)

AUCBG(1-3h): area under the blood glucose (BG) concentration-time profile
from 1-3 hours post-dose (i.e. from 0-2 hours after starting the OGTT)

E.5.1.1

Timepoint(s) of evaluation of this end point

With occasion of each of the 8 investigations

E.5.2

Secondary end point(s)

AUCBG(0-1h)
area under the blood glucose concentration-time profile from
0-1 hour post-dose (i.e. before starting the OGTT)
AUCBG(1-5h)
area under the blood glucose concentration-time profile from
1-5 hours post-dose (i.e. 0-4h after starting the OGTT)
AUCBG(1-1.5h)
area under the blood glucose concentration-time profile from
1-1.5 hours post-dose (i.e. from 0-30 min after starting the
OGTT)

Pameters after starting the OGTT:
ΔBGmax
BGmax
tBGmax
AUCINS(0-1h)
AUCINS(1-1.5h)
AUCINS(1-3-5h)
AUCINS(1-5h)
INSmax
INSmean
tINSmax

AUCGGN(1-5h)
area under the glucagon concentration-time profile from 1-5 hours post-dose (i.e. from 0-4 hours after starting the OGTT)

ΔGGN(0-1h)
glucagon excursions from 0-1 hour post-dose (i.e. before OGTT)

AUCBG(1-1.5h)xAUCINS(1-1.5h)
hepatic insulin resistance index

ΔGlucose120-300min/Δt x INSmean
muscle insulin sensitivity index

E.5.2.1

Timepoint(s) of evaluation of this end point

With occasion of each of the 8 investigations

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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

2013-10-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-09-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-04-01

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