Clinical Trials Register

Summary
EudraCT Number:	2011-001245-32
Sponsor's Protocol Code Number:	PGX-III-AP-002
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:	2011-07-11
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

Netherlands - Competent Authority

A.2

EudraCT number

2011-001245-32

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind Trial of Apadenoson for the Detection of Myocardial Perfusion Defects Using Single-Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging (MPI)

A.3.1

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

This is a trial of apadenoson, an investigational drug, for the detection of Myocardial Perfusion Defects using Single Photon Emission Computed Tomography Myocardial Perfusion Imaging (SPECT-MPI).

A.3.2

Name or abbreviated title of the trial where available

ASPECT-2

A.4.1

Sponsor's protocol code number

PGX-III-AP-002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01313572

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	Forest Laboratories, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Forest Laboratories, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Forest Research Institute, a subsidiary of Forest Laboratories, Inc.
B.5.2	Functional name of contact point	David B. Bharucha, MD, PhD, FACC
B.5.3	Address:
B.5.3.1	Street Address	Harborside Financial Center, Plaza V, Suite 1900
B.5.3.2	Town/ city	Jersey City
B.5.3.3	Post code	NJ 07311
B.5.3.4	Country	United States
B.5.4	Telephone number	001201-427-8647
B.5.5	Fax number	-
B.5.6	E-mail	david.bharucha@frx.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	Apadenoson-DP
D.3.2	Product code	apadenoson
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	apadenoson-DP
D.3.9.1	CAS number	250386-15-3
D.3.9.3	Other descriptive name	4-{3-[6-Amino-9-((2R,3R,4S,5S)-5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester; Cyclohexanecarboxylic acid, 4-[3-[6-amino-9-[N-ethyl-β-D- ribofuranuronamidosyl)-9H-purin-2-yl]-2-propynyl - methyl ester, ]- trans; Methyl trans-4[3[6-amino-9-(N-ethyl-β-D- ribofuranosyluronamide)-9H-purin-2-yl] prop -2-ynyl]cyclohexanecarboxylate
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	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	ADENOSCAN® 30 mg/10 ml, solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-aventis
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	adenosine
D.3.4	Pharmaceutical form	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	Adenosine
D.3.9.1	CAS number	58-61-7
D.3.9.4	EV Substance Code	SUB00297MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
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	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous bolus use (Noncurrent)
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	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

Coronary Artery Disease

E.1.1.1

Medical condition in easily understood language

Heart Disease

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	PT
E.1.2	Classification code	10011078
E.1.2	Term	Coronary artery disease
E.1.2	System Organ Class	10007541 - Cardiac 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 demonstrate non-inferiority between the level of agreement in diagnosis (i.e. patient
classification of normal, mild/moderate or severe ischemic disease based on the number of
reversible perfusion segments) between sequential adenosine SPECT-MPI versus sequential
SPECT-MPI with adenosine and apadenoson.

E.2.2

Secondary objectives of the trial

Secondary Gatekeeper Objectives
To demonstrate a statistically significant reduction with apadenoson treatment compared with adenosine treatment in the following treatment emergent AEs:
• Incidence of dyspnea
• VAS Symptom-Intensity Measure of dyspnea
• Incidence of flushing
• VAS Symptom-Intensity Measure of flushing
• Incidence of chest pain
• VAS Symptom-Intensity Measure of chest pain
• Incidence of headache
• VAS Symptom-Intensity Measure of headache
• Incidence of nausea
• VAS Symptom-Intensity Measure of nausea
• Incidence of dizziness
• VAS Symptom-Intensity Measure of dizziness
• Incidence of abdominal discomfort
• VAS Symptom-Intensity Measure of abdominal discomfort

Other Secondary Objectives (refer to protocol)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be considered for inclusion in this study:
• Referred for a clinically indicated rest /pharmacologic stress SPECT-MPI study
• Male or female subject, 18 years of age or older
• Must be able to provide written informed consent to participate before beginning any trial related activities
• Must be able to communicate effectively with trial personnel
• Subjects must have either high pretest probability of CAD based on age and gender and chest pain symptomatology assessed using the ACC/AHA guidelines for relative risk
OR
Have previously demonstrated known coronary artery disease based on medical history of prior myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or diagnostic angiogram demonstrating 50% or greater stenosis in one or more vessel, as well as reporting chest pain indicative of angina or anginal equivalents within the month prior to Pre-Study Evaluation (based on ACC criteria, e.g. dyspnea or extreme fatigue).
• Can safely abstain from caffeine or methylxanthine containing foods for 24 hours, from dipyridamole for 24 hours, and from theophylline and methylxanthine containing medications for at least 72 hours (or 4 half-lives, whichever is longer)
• Cardiovascular medication routine must remain stable from the time of signed informed consent through the Period 2 SPECT-MPI
• If female, be (a) at least one year post menopausal or surgically sterile or (b) nonpregnant (as determined by a negative urine β-hCG pregnancy test within 24 hours before each period imaging session), and (c) non-lactating. Women of childbearing potential (WOCBP) must have been practicing a medically approved method of birth control since their last menstrual period and be willing to utilize adequate contraception and not become pregnant during the full course of the study. Adequate contraception is defined as continuous use of 1 of the following:
o Norplant® (inserted at least 3 months prior to administration)
o Medroxyprogesterone acetate injection (given >14 days prior to signed informed consent)
o Oral contraception (stable use for 2 or more cycles prior to the time of signed informed consent and throughout the study)
o Double-barrier method (e.g., condom or diaphragm plus spermicide, sponge, foam or jelly)
o Intrauterine device (IUD, inserted >4 weeks prior to the time of signed informed consent)
o Monogamous partner with a bilateral vasectomy (procedure performed >3 months prior to the time of signed informed consent)
o Bilateral tubal ligation
o Abstinence

E.4

Principal exclusion criteria

Subjects meeting any of the following exclusion criteria will not be included in the study:
• Ingestion of a caffeinated or methylxanthine food substance (e.g. chocolate, cocoa) within 24 hours before receiving apadenoson or adenosine
• Treatment with dipyridamole within 24 hours, or theophylline, aminophylline, or pentoxifylline within 72 hours (or 4 half-lives, whichever is longer) prior to receiving apadenoson or adenosine
• Exposure to any investigational drug or device within 30 days prior to the time of signed informed consent
• Acute MI, new onset of ischemia or PCI within 30 days prior to SPECT-MPI at either Period 1 or Period 2; or CABG within 90 days prior to SPECT-MPI at either Period 1 or Period 2
• Any prior allergic response to aminophylline, adenosine, Tc99m Sestamibi, Thallium 201 or Tc99m Tetrofosmin or any of their components or other contraindication to pharmacologic stress testing with adenosine
• Active severe asthma or severe chronic obstructive pulmonary disease (COPD) which, in the Investigator’s opinion, places the subject at risk for severe bronchoconstriction
• History or evidence of clinically significant high grade AV block (including type 2 second or third degree block) or sinus node disease, such as sick sinus syndrome or symptomatic bradycardia, in the absence of a functioning permanently implanted pacemaker
• Evidence of hemodynamically significant valvular disease or outflow tract obstruction
• Uncontrolled severe hypertension or malignant ventricular arrhythmias
• Current significant illness or disorder including significant laboratory abnormalities, ECG abnormalities, or other pathology that could potentiate any adverse pharmacological event associated with a vasodilating drug or any abnormality that, in the opinion of the Investigator, could put the subject at risk
• Pretreatment hypotension (systolic BP < 90 mm Hg) or tachycardia (HR > 100 bpm)
• Known history of cerebral vascular accident or suspected transient ischemic attack within 30 days prior to signed informed consent
• Psychological or addictive disorder which may interfere with an ability to provide informed consent

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the level of agreement of diagnosis (i.e. patient classification of normal, mild/moderate or severe ischemic disease based on the number of reversible perfusion segments) between sequential adenosine SPECT-MPI versus the level of agreement in diagnosis between an adenosine and an apadenoson SPECT-MPI.

E.5.1.1

Timepoint(s) of evaluation of this end point

Period 1 SPECT-MPI 7 +/-7 days following pre-study evaluation.
Period 2 SPECT-MPI to be taken within 9 +/- 6 days after Period 1 SPECT-MPI.

E.5.2

Secondary end point(s)

Secondary Gatekeeper Objective:
To demonstrate a statistically significant reduction with apadenoson treatment compared with adenosine treatment in the incidence and intensity measure of dyspnea, flushing, chest-pain, headache, nausea, dizziness and, abdominal discomfort.

Other Secondary Objectives:
• Assessment of adverse events (AEs), change in laboratory findings, physical examinations, vital signs, ECGs and number of discontinuations due to AEs
•Incidence of atrioventricular (AV) block
•Subject-rated Treatment experience
• Agreement of Median Summed Stress Scores (SSS)
• Interpretation of Wall Motion
• Agreement of Extent of Ischemia
• Comparison of Sensitivity and Specificity
• Image Quality, Myocardial Region, Diagnostic Certainty and Overall Findings
• Detection of Perfusion Defects According to Coronary Artery Territory

• Estimate PK parameters of Apadenoson and ATL146a

E.5.2.1

Timepoint(s) of evaluation of this end point

Period 1 SPECT-MPI 7 +/-7 days following pre-study evaluation.
Period 2 SPECT-MPI to be taken within 9 +/- 6 days after Period 1 SPECT-MPI.

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

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

Yes

E.8.1.7.1

Other trial design description

double-dummy

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

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

Belgium

Brazil

Netherlands

United States

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

Last Visit, Last Subject

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