Clinical Trials Register

Summary
EudraCT Number:	2012-004799-21
Sponsor's Protocol Code Number:	KCT03/2012
National Competent Authority:	Slovenia - JAZMP
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-11-26
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

Slovenia - JAZMP

A.2

EudraCT number

2012-004799-21

A.3

Full title of the trial

The Efficacy and Safety of ROSUvastatin Dose Titration in the Treatment of PATients with Hyperlipidemia (ROSU-PATH)

A.3.1

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

The efficacy and safety of a medicine containing the active substance rosuvastatin

A.3.2

Name or abbreviated title of the trial where available

ROSU-PATH

A.4.1

Sponsor's protocol code number

KCT03/2012

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	Krka, d.d., Novo mesto
B.1.3.4	Country	Slovenia
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	Krka, d.d., Novo mesto
B.4.2	Country	Slovenia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Krka, d.d., Novo mesto
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Dunajska cesta 65
B.5.3.2	Town/ city	Ljubljana
B.5.3.3	Post code	1000
B.5.3.4	Country	Slovenia
B.5.4	Telephone number	38614751236
B.5.6	E-mail	tanja.kohek@krka.biz

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	Sorvasta
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, tovarna zdravil, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija
D.2.1.2	Country which granted the Marketing Authorisation	Slovenia
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	No
D.3.7	Routes of administration for this IMP	Oral use
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	Sorvasta
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, tovarna zdravil, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija
D.2.1.2	Country which granted the Marketing Authorisation	Slovenia
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	No
D.3.7	Routes of administration for this IMP	Oral use
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: 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	Yes
D.2.1.1.1	Trade name	Sorvasta
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, tovarna zdravil, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija
D.2.1.2	Country which granted the Marketing Authorisation	Slovenia
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	No
D.3.7	Routes of administration for this IMP	Oral use
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: 4
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	Sorvasta
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, tovarna zdravil, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija
D.2.1.2	Country which granted the Marketing Authorisation	Slovenia
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	No
D.3.7	Routes of administration for this IMP	Oral use
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: 5
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	Sorvasta
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, tovarna zdravil, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija
D.2.1.2	Country which granted the Marketing Authorisation	Slovenia
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	No
D.3.7	Routes of administration for this IMP	Oral use
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with primary hypercholesterolemia and mixed dyslipidemia (type IIb)

E.1.1.1

Medical condition in easily understood language

patients with primary hypercholesterolemia and mixed dyslipidemia (type IIb) - patients with high absolute risk for cardiovascular diseases in primary and secondary prevention

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10020604
E.1.2	Term	Hypercholesterolemia
E.1.2	System Organ Class	100000004861

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10071235
E.1.2	Term	Combined hyperlipidemia
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of the study is to establish the efficacy and safety of Sorvasta in wide populations of patients with primary hypercholesterolemia and mixed dyslipidemia (type IIb) (patients with high absolute risk for cardiovascular diseases in primary and secondary prevention) with emphasis on placement of additional strengths 15 mg and 30 mg in clinical practice.

E.2.2

Secondary objectives of the trial

To demonstrate linear association between doses and reduction of LDL-c.
To compare the differences between group treated according to usual clinical practise (standard titration: 10 mg – 20 mg – 40 mg) and a group treated according to alternative scheme: 15 mg – 30 mg – 40 mg.
To evaluate percentage change in HDL-c, TC and TG, from baseline at all time points (4, 8, 12 weeks).
To evaluate percentage of patients achieving the 2011 ESC/EAS guidelines LDL-c goal at all time points (4, 8, 12 weeks).
To quantify the rate of adverse reactions associated with treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients of both genders with primary hypercholesterolemia or mixed dyslipidemia (type IIb), when the response to diet and other non-pharmacological measures has been inadequate.
Age 18 years to 75 years.
Written informed consent provided by patients or legally acceptable representative.
Absence of hypolipidemic therapy during not less than 4 weeks prior to the 1st visit.

E.4

Principal exclusion criteria

• Serum TG values exceeding 4.5 mmol/l.
The aim of the study is to exclude patients with predominant hypertriglyceridemia or with severe combined hyperlipidemia because of their influence on the evaluation of results.
• TC values exceeding 10 mmol/l.
This criterion will be used to exclude from the study patients with severe hypercholesterolemia, including homozygote familial hypercholesterolemia.
• Secondary hyperlipidemia due to hypothyroidism, nephrotic syndrome, type I diabetes mellitus, obstructive gallbladder, biliary disease, pancreatitis, immunologic abnormalities, or drug induced.
• Hypersensitivity to rosuvastatin or to any of the excipients.
• Active liver disease, including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN).
• Severe renal impairment (creatinine clearance < 30 ml/min or 0.5 ml/s).
• Statin induced myopathy (an abnormal condition of skeletal muscle characterized by muscle weakness, wasting, and histologic changes within muscle tissue) that can present as myalgia (muscle aches or weakness without creatinine kinase (CK) elevation) or rhabdomyolysis (muscle symptoms with marked CK elevation more than 5 times the upper limits of normal).
• Treatment with the following drug: cyclosporine, other lipid-lowering medicines (statins, fibrates, nicotinic acid, bile acid exchangers, probucol, ezetimibe).
• Pregnancy and lactation and childbearing potential in women not using appropriate contraceptive measures.
• Pathological clinical states that could affect patient’s compliance, or have any impact on patient’s survival rate (malignant diseases, alcohol abuse, medicine addiction, psychiatric diseases).
• Acute disease state (infections, acute exacerbation of chronic diseases, trauma, surgical intervention) within the period of the past two months.
• Severe, unstable heart failure.
• Participation in another clinical trial within thirty days prior to enrolment.
• Patients who are not able out of any reason to fulfill the requirements of the protocol.

E.5 End points

E.5.1

Primary end point(s)

• To evaluate efficacy of Sorvasta in achieving 2011 ESC/EAS guidelines target LDL-c levels in patients with hyperlipidemia. 2011 ESC/EAS guidelines LDL-c goals: 1.8, 2.5 or 3.0 mmol/l, depending on risk category or a ≥ 50% reduction from baseline LDL-c when target lipid level could not be reached for very high risk patients.

E.5.1.1

Timepoint(s) of evaluation of this end point

4, 8, 12 weeks

E.5.2

Secondary end point(s)

• To demonstrate linear association between doses and reduction of LDL-c.
• To compare the differences between group treated according to usual clinical practice (standard titration: 10 mg – 20 mg – 40 mg) and a group treated according to alternative scheme: 15 mg – 30 mg – 40 mg.
• To evaluate percentage change in HDL-c, TC and TG, from baseline at all time points (4, 8, 12 weeks).
• To evaluate percentage of patients achieving the 2011 ESC/EAS guidelines LDL-c goal at all time points (4, 8, 12 weeks).
• To quantify the rate of adverse reactions associated with treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

4, 8, 12 weeks

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Different dose of the same product.

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

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

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

Croatia

Czech Republic

Romania

Russian Federation

Slovenia

Ukraine

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

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:

400

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

140

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

310

F.4.2.2

In the whole clinical trial

540

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 trial, patients should continue the treatment in accordance with the treatment doctrine and guidelines.

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

2013-02-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-05

P. End of Trial
P.	End of Trial Status	Completed

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