Clinical Trials Register

Summary
EudraCT Number:	2007-000860-25
Sponsor's Protocol Code Number:	CSPP100E2337
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:	2007-08-06
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

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

A clinical trial 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.3.2

Name or abbreviated title of the trial where available

ALTITUDE: ALiskiren Trial In Type 2 diabetes Using cardio-renal Disease Endpoints

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 GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice
B.5.3	Address:
B.5.3.1	Street Address	Roonstr. 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+491802232300
B.5.5	Fax number	+4991127312160
B.5.6	E-mail	infoservice.novartis@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 150 mg film-coated tablets
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 300 mg Film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Novatis 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
Micro-albuminuria
Macro-albuminuria
Reduced estimated glomerular filtration rate

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

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

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

- Type 1 diabetes mellitus
- Cardiovascular event or procedure ≤ 3 months prior to Visit 1
- Unstable serum creatinine
- Hypertension: Mean sitting systolic blood pressure (msSBP) ≥ 135 and
< 170 mmHg or Mean sitting diastolic blood pressure (msDBP) ≥ 85 and
< 110 mmHg unless treated with at least 3 antihypertensive medications
- Hypertension msSBP ≥ 170 or msDBP ≥ 110 mmHg
- Baseline Serum Potassium > 5.0 mmol/L
- Patients who are treated with two renin-angiotensin-aldosteronesystem-
blockers
- Patients with NYHA class III or IV heart failure
- Known renal artery stenosis
- Previous randomization into the AVOID trial (CSPP100C2201)
- 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

Other protocol-defined inclusion/exclusion criteria may apply.

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)

Time from randomization to the first event of the following composite CV
endpoint:
Cardiovascular (CV) death
Resuscitated sudden death
Non-fatal myocardial infarction (MI)
Non-fatal stroke
Unplanned hospitalization for heart failure (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.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.8.3

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

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

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

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.1.2.1

Number of subjects for this age range:

3977

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

4295

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

300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

4400

F.4.2.2

In the whole clinical trial

8600

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)

Following the data monitoring committee recommendation, all patients
were required to permanently discontinue study drug by 6 Jan 2012. A
12 month safety follow-up period post study drug discontinuation is
implemented upon request of the CHMP. Depending on the study drug
discontinuation date, the patients can have up to 4 safety visits,
occurring at 3 month intervals, to cover the 12 month follow-up period.

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

2007-10-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-10-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-02-06

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