Clinical Trials Register

Summary
EudraCT Number:	2006-005047-28
Sponsor's Protocol Code Number:	CS0011-A-U301
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-03-05
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

UK - MHRA

A.2

EudraCT number

2006-005047-28

A.3

Full title of the trial

A RANDOMIZED, DOUBLE-BLIND, PLACEBO AND ACTIVE COMPARATOR-CONTROLLED,
PARALLEL-GROUP STUDY OF THE EFFICACY AND SAFETY OF RIVOGLITAZONE AS MONOTHERAPY TREATMENT OF TYPE 2 DIABETES MELLITUS

A.4.1

Sponsor's protocol code number

CS0011-A-U301

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	DAIICHI SANKYO PHARMA DEVELOPMENT
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
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	Rivoglitazone
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	rivoglitazone
D.3.9.1	CAS number	299176-11-7
D.3.9.2	Current sponsor code	CS-011
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	1
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	Actos 45 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Global Research and Development Centre (Europe) Ltd
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	Pioglitazone
D.3.4	Pharmaceutical form	Capsule*
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.3.9.3	Other descriptive name	Actos
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	45
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: 3
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	Rivoglitazone
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	rivoglitazone
D.3.9.1	CAS number	299176-11-7
D.3.9.2	Current sponsor code	CS-011
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	1.5
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.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
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule*
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
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

The current study will support an indication for rivoglitazone as oral monotherapy to improve glycemic control in subjects with type 2 diabetes mellitus not adequately controlled with diet and exercise alone.

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

1. To compare the effects on mean change from baseline in A1C, for rivoglitazone, versus pioglitazone, administered as monotherapy in type 2 diabetics over a 26-week treatment period.

E.2.2

Secondary objectives of the trial

2. To demonstrate the safety and tolerability of rivoglitazone as a treatment for type 2 diabetes mellitus.

3. To demonstrate the lowering of FPG with rivoglitazone, versus placebo, over 26 weeks in type 2 diabetics.

4. To assess the effects of each rivoglitazone dose on the percent of responders as defined by:
- Subjects experiencing a decrease of ≥ 0.7 percentage units in A1C
- Subjects achieving an A1C goal of < 7.0 %
- Subjects achieving an A1C goal of < 6.5 %

5. To assess the effect of rivoglitazone versus placebo, on HOMA indices of insulin resistance and β-cell function in type 2 diabetics.

6. To assess the effects of rivoglitazone on change from baseline and percent change from baseline in plasma lipids (including TC, LDL-C, HDL-C and TG, and on parameters including adiponectin, hs-CRP, insulin, Apo A1 and Apo B).

7. To compare effects of rivoglitazone versus pioglitazone on secondary measures of glycemic control and lipid parameters.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Willing and able to give written informed consent
at screening.
• Diagnosis of Type 2 diabetes.
• Male or female subjects ≥ 18 years of age.
• A1C > 7.0% and ≤ 8.5% at screening.
• Women of childbearing potential (WOCBP) must
be using an adequate method of contraception as
detailed per-protocol to avoid pregnancy
throughout the study, and for up to 4 weeks after
study completion (see Section 5.4.2).
• Non-fasting C-peptide >0.5 ng/mL at screening.
• Subjects currently treated with a stable dose of an
approved non-thiazolidinedione
antihyperglycemic medication (including
sulfonylureas, meglitinides, insulin secretagogues,
metformin, or α-glucosidase inhibitors) given as
monotherapy, for at least 3 months prior to
screening.
OR
• Subjects untreated with any antihyperglycemic
agent during the 2 months prior to screening and
with no prior history of treatment failure with, or intolerance of, a thiazolidinedione.
The target enrollment for untreated or treatmentnaïve
subjects is at least 20%.
• If not treated with an oral antihyperglycemic agent, subject is considered to have
failed diet and exercise modification as the sole treatment for type 2 diabetes.
• Clinically stable in regards to medical conditions other than type 2 diabetes.
• Concomitant medications (other than oral antihyperglycemic agents; see # 7), are
at stable doses for at least 30 days prior to enrollment, and are not anticipated to
need adjustment during the study period.

E.4

Principal exclusion criteria

• A history of Type 1 diabetes or ketoacidosis.
• History of long-term (>2 months) therapy
with insulin.
• At least two (≥2) readings of fasting blood
glucose (FBG) >240 mg/dL (13.3 mmol/L)
during the 2 week washout/stabilization and
placebo run-in period (Period A).
• Systolic blood pressure (SBP) ≥ 180 mmHg
and/or diastolic blood pressure (DBP) ≥ 110
mmHg.
• Any known history of congestive heart failure
(CHF).
• Impaired hepatic function (including active
hepatitis and/or elevated liver enzymes as
specified per protocol).
• A history of prior treatment failure with, or
intolerance of, a thiazolidinedione.
• Contraindication to treatment with 45 mg
pioglitazone QD.
• Treatment with fibrates (eg, fenofibrate,
gemfibrozil).
• Body mass index (BMI) >45 kg/m2.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Analysis
The primary comparisons in this study is simultaneous evaluation of non-inferiority and superiority for each descending dose of rivoglitazone versus 45 mg pioglitazone, and superiority assessment for each descending dose of rivoglitazone versus placebo, with respect to the mean change from baseline in glycosylated hemoglobin (A1C), when administered as monotherapy over a 26 week treatment period. An assessment of non-inferiority and superiority for 1.5 mg rivoglitazone versus 45 mg pioglitazone will be evaluated first, and if significant, a non-inferiority and superiority analyses for 1.0 mg rivoglitazone versus 45 mg pioglitazone as well as superiority analysis for 1.5 mg rivoglitazone versus placebo will be performed. Lastly, if superiority is shown for 1.5 mg rivoglitazone versus placebo, superiority will be tested for 1.0 mg rivoglitazone versus placebo. It is acknowledged, however, that power for assessing superiority for 1.0 mg rivoglitazone versus 45 mg pioglitazone is low due to smaller numbers of planned enrollment in the 1.0 mg rivoglitazone arm (ie, n=260). Testing hypotheses in this pre-specified tree-structured hierarchically ordered manner will preserve the family-wise type I error rate at 0.05.12.

The primary efficacy analyses will be adjusted for the effects of the stratification factors using the appropriate methods (eg, generalised Cochran-Mantel-Haenszel [CMH] method, analysis of covariance [ANCOVA] method, etc) and the detailed algorithm will be described in the statistical analysis plan.

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

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

Yes

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

last patient last visit

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

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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

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

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

451

F.4.2.2

In the whole clinical trial

1820

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)

After the end of the study the patients will receive normal standard treatment

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

2007-02-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-11-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2009-02-12

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