Clinical Trials Register

Summary
EudraCT Number:	2010-024249-59
Sponsor's Protocol Code Number:	ULA01
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-09-21
Trial 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

Netherlands - Competent Authority

A.2

EudraCT number

2010-024249-59

A.3

Full title of the trial

Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Ularitide (Urodilatin) Intravenous Infusion in Patients Suffering from Acute Decompensated Heart Failure [TRUE-AHF]

A.3.1

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

Treatment of Acute Heart Failure

A.4.1

Sponsor's protocol code number

ULA01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01661634

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	Cardiorentis Ltd.
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	Cardiorentis Ltd
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	Cardiorentis
B.5.2	Functional name of contact point	Dr Johannes Holzmeister
B.5.3	Address:
B.5.3.1	Street Address	Steinhauserstr. 74
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	CH-6300
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41417486030
B.5.6	E-mail	jholzmister@cardiorentis.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	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	Ularitide-2.5mg
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ULARITIDE
D.3.9.1	CAS number	118812-69-4
D.3.9.4	EV Substance Code	SUB11377MIG
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	2.5
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)	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	Lyophilisate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Decompensated Heart Failure

E.1.1.1

Medical condition in easily understood language

Acute Heart Failure

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10064653
E.1.2	Term	Acute decompensated heart failure
E.1.2	System Organ Class	100000004849

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 evaluate the effect of a continuous intravenous (IV) ularitide infusion on the clinical status of patients with ADHF.

E.2.2

Secondary objectives of the trial

Not applicable

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

Pharmacokinetic substudy in association with study ULA01 – Determination of plasma pharmacokinetic parameters and population pharmacokinetic model

Pharmacoeconomic substudy in association with study ULA01 – Determination of pharmacoeconomic aspects in treatment of ADHF

E.3

Principal inclusion criteria

1) Males and females aged 18 to 85 years.
2) Unplanned hospitalization or emergency department visit for ADHF. Acute HF is defined as including all of the following:
a) Dyspnea at rest in a recumbent sitting position (30 to 45 degrees), which has worsened within the past week.
b) Radiological evidence of HF on a chest X-ray (if an appropriate chest computerized tomography scan is done; the X-ray need not be performed).
c) Brain natriuretic peptide (BNP) >500 pg/mL or NT-pro BNP >2000 pg/mL.
3) Ability to start infusion of the study drug within 12 h after initial clinical assessment performed by a physician at the emergency room/hospital.
4) Ability to reliably carry out self-assessment of symptoms.
5) Systolic blood pressure (SBP) ≥116 mmHg and ≤ 180 mmHg at the time of randomization.
6) Persisting dyspnea at rest despite standard background therapy for ADHF (as determined by the Investigator) which must include IV furosemide (or equivalent diuretic) at ≥40 mg (or its equivalent) at any time after start of emergency services (ambulance, emergency department, or hospital). At the time of randomization, the patient must still be symptomatic. In addition, the patient should not have received an IV bolus of a diuretic for at least 2 h prior to randomization, and the infusion rates of ongoing IV infusions of medication to treat HF must not have been increased or decreased for at least 2 h prior to randomization.
7) Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local privacy regulations).

E.4

Principal exclusion criteria

1) Known active myocarditis, obstructive hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, constrictive pericarditis, uncorrected clinically significant primary valvular disease.
2) Treatment with dobutamine at a dose >5 μg/kg/min or use of drugs for support of BP at the time of randomization.
3) Treatment with levosimendan, milrinone, or any other phosphodiesterase inhibitor within 7 days before randomization.
4) Treatment with nesiritide within 30 days before randomization.
5) Creatinine clearance <25 mL/min/1.73m² (as measured by the MDRD formula) at the time of screening.
6) Planned coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting) within 5 days of randomization.
7) Clinical diagnosis of acute coronary syndrome meeting any 2 of the following 3 criteria:
a) Prolonged chest pain at rest, or an accelerated pattern of angina;
b) Electrocardiogram (ECG) changes indicative of ischemia or myocardial injury, defined as:a new ST elevation at the J point of two anatomically contiguous leads with the cut-off points: ≥0.2 mV in men ≥ 40 years ( >0.25 mV in men >40 years) or ≥0.15 mV in women in leads V2-V3 and/or ≥0.1 mV in other leads;or ST depression and T wave changes. New horizontal or down-sloping ST depression ≥0.05 mV in two contiguous leads; and/or new T inversion ≥0.3 mV in two contigious leads;
c) Serum troponin >3 times upper limit of normal.
8) Clinically suspected acute mechanical cause of ADHF (e.g., papillary muscular rupture). The diagnosis need not be confirmed by imaging or cardiac catheterization.
9) Anemia (hemoglobin <9 g/dL or a hematocrit <25%).
10) Known vasculitis, active infective endocarditis, or suspected infections including pneumonia, acute hepatitis, systemic inflammatory response syndrome, or sepsis.
11) Body temperature ≥38°C just prior to randomization.
12) Acute or chronic respiratory disorder (e.g. severe chronic obstructive pulmonary disease) or primary pulmonary hypertension sufficient to cause dyspnea at rest, which may interfere with the ability to interpret dyspnea assessments or hemodynamic measurements.
13) Terminal illness other than congestive heart failure with expected survival <180 days.
14) Any previous exposure to ularitide.
15) Known allergy to natriuretic peptides.
16) Participation in an investigational clinical drug trial within 30 days prior to randomization.
17) Current drug abuse or chronic alcoholism sufficient to impair participation and compliance to the study protocol.
18) Women who are breast-feeding.
19) Women of child-bearing potential (i.e. pre-menopausal women) without documentation of a negative urine/blood pregnancy assay within 12 h prior to randomization.
20) Any condition that, in the Investigator's opinion, makes the patient unsuitable for study participation.
21) Legal incapacity or limited legal capacity.
22) Patients requiring mechanical circulatory support.
23) Patients with severe hepatic impairment.

E.5 End points

E.5.1

Primary end point(s)

There are two co-primary endpoints.
Co-primary efficacy endpoint 1 evaluates changes in a hierarchical clinical composite comprising: patient global assessment using a 7-point scale of symptomatic improvement, lack of improvement, or worsening; persistent or worsening heart failure (HF) requiring initiation or intensification of IV therapy, circulatory or ventilatory mechanical support, surgical intervention, ultrafiltration, hemofiltration or dialysis; and all-cause mortality. Assessment of the clinical composite will be performed at 6 hour (h), 24 h and 48 h after start of IV ularitide infusion.
Patients will be classified as “improved” if the patients are moderately or markedly improved at all 3 time points (at 6 h, 24 h and 48 h) and do not fulfill criteria for “worse” during the first 48 hours following the start of the study drug infusion. Patients will be classified as “worse” if (during the 48 h) they die; experience persistent or worsening HF requiring an intervention at any time during the first 48 h; or experienced moderate or marked worsening of their global assessment at any of the 3 time points (at 6 h, 24 h or 48 h).
Co-primary efficacy endpoint 2 evaluates freedom from cardiovascular mortality during follow-up after randomization, for the entire duration of the trial.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary Efficacy Endpoint:
3 time points (at 6 h, 24 h or 48 h).

E.5.2

Secondary end point(s)

Secondary Endpoints:
•Length of stay of index hospitalization in hours after start of study drug infusion up to 30 days.
•Length of stay in intensive care (intensive care unit [ICU] or critical care unit [CCU]) during the first 120 h following the start of the study drug infusion.
•Number of events of persistent or worsening HF requiring an intervention from the start of the study drug infusion to 120h.
•Proportion of patients with persistent or worsening HF and requiring an intervention from the start of study drug infusion to 120 h.
•Reduction in rehospitalization for heart failure within 30 days after initial hospital discharge.
•Change of N-terminal pro-brain natriuretic peptide (NT-pro BNP) at 48h of treatment compared to baseline.
•Time to completion of last dose of any IV drugs that can be used for the treatment of HF (e.g., diuretics, vasodilators, or positive inotropic agents) for the first 120 h following the start of the drug infusion.
•Change in serum creatinine from baseline through 72 h.
•Combined all-cause mortality or cardiovascular rehospitalization through Day 180 after start of study drug infusion, including patients still hospitalized at Day 30.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary Endpoints:
• 48 h of treatment.
• Day 90 after start of study drug infusion.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

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)

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

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

120

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

Brazil

Canada

Chile

Colombia

Czech Republic

Denmark

Estonia

Finland

France

Germany

Hungary

Italy

Latvia

Lithuania

Netherlands

Poland

Romania

Serbia

Sweden

Switzerland

Tunisia

Turkey

United States

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

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:

1076

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1076

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-09-21.

Yes

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

Yes

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

1061

F.4.2.2

In the whole clinical trial

2152

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

2012-09-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-22

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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