Clinical Trials Register

Summary
EudraCT Number:	2007-000860-25
Sponsor's Protocol Code Number:	CSPP100E2337
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-09-12
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

Lithuania - SMCA

A.2

EudraCT number

2007-000860-25

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, parallel-group study to determine whether, in patients with type 2 diabetes at high risk for cardiovascular and renal events, aliskiren, on top of conventional treatment, reduces cardiovascular and renal morbidity and mortality

A.3.1

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

Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints

A.3.2

Name or abbreviated title of the trial where available

ALTITUDE

A.4.1

Sponsor's protocol code number

CSPP100E2337

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma Services Inc. representative office in Lithuania
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Konstitucijos av. 7
B.5.3.2	Town/ city	Vilnius
B.5.3.3	Post code	LT-09308
B.5.3.4	Country	Lithuania
B.5.4	Telephone number	+3705269 1650
B.5.5	Fax number	+370 5249 6338
B.5.6	E-mail	DRA.Lithuania@novartis.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	Rasilez
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd.
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	Aliskiren
D.3.2	Product code	SPP100
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	Aliskiren
D.3.9.1	CAS number	173334-57-1
D.3.9.2	Current sponsor code	SPP100
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	150
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	Rasilez
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Ltd.
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	Aliskiren
D.3.2	Product code	SPP100
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	Aliskiren
D.3.9.1	CAS number	173334-57-1
D.3.9.2	Current sponsor code	SPP100
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	300
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
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

Type 2 diabetes mellitus
Cardiovascular disease
Micro-albuminuria
Macro-albuminuria
Reduced estimated glomerular filtration rate

E.1.1.1

Medical condition in easily understood language

Type 2 diabetes Mellitus; cardiovascular Disease

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10018358
E.1.2	Term	Glomerular filtration rate decreased
E.1.2	System Organ Class	10022891 - Investigations

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	10045242
E.1.2	Term	Type II diabetes mellitus
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	10007648
E.1.2	Term	Cardiovascular disease, unspecified
E.1.2	System Organ Class	100000004849

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10027525
E.1.2	Term	Microalbuminuria
E.1.2	System Organ Class	10038359 - Renal and urinary 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

To determine whether aliskiren, compared to placebo, when added to conventional treatment, delays the occurrence of cardiovascular and renal complications in patients with type 2 diabetes at high risk for cardiovascular and renal events.

For details on definition of cardiovascular or renal complications, please refer to the protocol.

E.2.2

Secondary objectives of the trial

• To determine whether aliskiren, compared to placebo, when added to
conventional treatment delays the occurrence of cardiovascular complications. For details on definition of cardiovascular complications, please refer to the protocol.
• To determine whether aliskiren, compared to placebo, when added to
conventional treatment delays the occurrence of renal complications. For details on definition of renal complications, please refer to the protocol.

Exploratory objectives:
For full list, please refer to the protocol.

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

Title: Exploratory pharmacogenetic and mRNA expression profiling sub-study for CSPP100E2337.
A randomized, double-blind, placebo-controlled, parallelgroup study to determine whether, in patients with type 2 diabetes at high risk for cardiovascular and renal events, aliskiren, on top of conventional treatment, reduces cardiovascular and renal morbidity and mortality.

Objective: a) examining whether individual genetic variation in genes relating to drug metabolism, type 2 diabetes with renal and cardiovascular risk, and the drug target pathway confer differential response to aliskiren and b) examining the effect of aliskiren on gene expression in peripheral blood cells in type2 diabetic patients at risk for renal and cardiovascular disease

date : 26-Mar-2007
version of substudy: 1st version

E.3

Principal inclusion criteria

For full list, please refer to the protocol

1. Patients with type 2 diabetes according to WHO definition
2. Male or female patients ≥ 35 years of age.
3. Patients who provide written informed consent to participate in the study
after the purpose and nature of the investigation have been clearly explained to
them
4. Patients with at least one of the following :
• Persistent macroalbuminuria (UACR ≥ 200 mg/g [or 22.6 mg/mmol] in at least
two out of three first morning void urine samples)
• Persistent microalbuminuria (UACR ≥ 20 mg/g and < 200 mg/g [or UACR ≥
2.26 mg/mmol and < 22.6 mg/mmol] in at least two of three morning void
urines) and a mean eGFR < 60 mL/min/1.73m2 calculated by the abbreviated
MDRD study equation (Levey, et al 2000) (mean of two consecutive
measurements)
• A history of cardiovascular disease and a mean eGFR < 60 mL/min/1.73m2
History of cardiovascular disease is defined as at least one of the following:
• Previous MI (previous hospitalization with a discharge diagnosis of MI)
• Previous stroke (previous hospitalization with a discharge diagnosis of
stroke. A previous transient ischemic attack -TIA- is not sufficient to fulfill this
criterion)
• HF (previous hospitalization with a discharge diagnosis of HF, with or without
preserved ejection fraction)
• Coronary artery disease (CAD) defined as follows:
• History of percutaneous coronary intervention [PCI]
• Coronary artery bypass graft [CABG]
• Angiographically proven stenosis ≥ 50% in at least one major epicardial
coronary artery
5. Patient's concomitant treatment must include an ACEI or an ARB. Patient should
be on conventional therapy according to national guidelines. Patients must not
have had any adjustments to their concomitant antihypertensive therapy for at
least four (4) weeks prior to randomization (Visit 3).

E.4

Principal exclusion criteria

For full list, please refer to the protocol
1. eGFR < 30 mL/min/1.73m2 as calculated by the abbreviated MDRD
study equation (mean of two consecutive measurements).
2. Serum potassium >5.0 mmol/L (at the visit directly preceding Visit 3). If the
investigator has reason to believe the serum potassium result is invalid, one repeat test may be done.
3. History of any cardiovascular event (stroke, transient ischemic cerebral attack, MI, unstable angina, CABG, percutaneous coronary intervention, hospitalization due to HF) during the 3 months prior to Visit 1.
• If a patient experiences such an event between Visit 1 and randomization at Visit 3, he/she should be withdrawn from the screening phase. If suitable, the patient can be re-screened at a later stage (see Section 5.2).
4. Hypertension (at Visit 3): any patient with a mean sitting systolic blood pressure (msSBP) ≥ 135 mmHg or msDBP ≥ 85 mmHg should be excluded unless treated with at least 3 anti-hypertensive medications; even if treated with 3 or more anti-hypertensive agents, a patient with msSBP ≥ 170 mmHg or msDBP ≥ 110 mmHg must be excluded.
5. Congestive heart failure NYHA class III or IV.
6. Concomitant treatment with two (2) or more renin-angiotensinaldosterone system blocking agents apart from the study drug, e.g. ACEI, ARB or aldosterone-antagonist or any renin inhibitor.
7. Unstable serum creatinine: defined as ≥ 20% difference between 2 consecutive serum creatinine measurements before Visit 3. A maximum of 4 measurements will be allowed. If the difference between the first 2 measurements is ≥ 20% of the higher value, a third measurement should be performed at the next visit. If the difference between the last 2 measurements is ≥ 20% of the
higher value, at fourth measurement should be performed at the next visit. If the difference
between the last two measurements performed is ≥ 20%, the patient is excluded.
8. Second or third degree heart block without a pacemaker.
9. Concurrent potentially life threatening arrhythmia or other uncontrolled arrhythmia.
10. Clinically significant valvular heart disease.

- Specific to the safety follow-up period: Aliskiren or aliskiren-containing fixed combination products must not be used in combination with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) in patients with diabetes.
- Specific to the safety follow-up period: Participation in another clinical trial, whether or not on investigational drug

E.5 End points

E.5.1

Primary end point(s)

Time from randomization to the first event of the following composite
endpoint:
Cardiovascular (CV) death
Resuscitated sudden death
Non-fatal myocardial infarction (MI)
Non-fatal stroke
Unplanned hospitalization for heart failure (HF)
Onset of end-stage renal disease (ESRD) defined as initiation of dialysis,
renal transplantation, or a serum creatinine concentration above 6.0
mg/dL (530 μmol per liter) or renal death
Doubling of baseline serum creatinine concentration to above the upper
limit of normal according to the central laboratory, sustained for at least
one month.

E.5.1.1

Timepoint(s) of evaluation of this end point

It will be calculated in days for each patient as the difference between
the date of the first event or censoring date if no event occurs and the
date of randomization visit (day 1) plus one.

E.5.2

Secondary end point(s)

To determine whether aliskiren, compared to placebo, when added to conventional
treatment delays the occurrence of cardiovascular complications, defined as the first event
of the following composite endpoint:
• CV death
• Resuscitated sudden death
• Non-fatal MI
• Non-fatal stroke
• Unplanned hospitalization for HF
Time from randomization to the first event of the following composite
renal endpoint:
Onset of end-stage renal disease (ESRD) defined as initiation of dialysis,
renal transplantation, or a serum creatinine concentration above 6.0
mg/dL (530 μmol per liter) or renal death
Doubling of baseline serum creatinine concentration to above the upper
limit of normal according to the central laboratory, sustained for at least
one month

E.5.2.1

Timepoint(s) of evaluation of this end point

All statistical analysis for exploratory efficacy will be performed at end of study on the Full Analysis Set (FAS).

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

483

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

Austria

Belgium

Brazil

Canada

China

Colombia

Czech Republic

Denmark

Estonia

Finland

France

Germany

Greece

Guatemala

India

Italy

Japan

Korea, Republic of

Netherlands

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

Study duration is between 2.5 years and 5.5 years. This includes a safety long-term follow-up phase. Following the recommendation of the DMC overseeing the trial all patients were required to discontinue study drug by 6 Jan 2012. A 12 month safety follow-up period post study drug discontinuation is implemented upon request of CHMP.

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