Clinical Trials Register

Summary
EudraCT Number:	2016-003586-26
Sponsor's Protocol Code Number:	CV013-020
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-03-12
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

Netherlands - Competent Authority

A.2

EudraCT number

2016-003586-26

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled, Cross-over Phase 2 Study of Continuous 5-Hour Intravenous Infusions of BMS-986231 in Patients with Heart Failure and Impaired Systolic Function

A.3.1

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

An international study at different study sites designed to evaluate the effects of BMS-986231 versus NTG versus placebo on systolic and diastolic parameters as measured by echocardiogrpahy. BMS-986231, NTG or Placebo are provided in the form of Intravenous Infusions for a duration of 5- hour in patients whose heart is unable to pump sufficiently (chronic heart failure); exposed to each of the 3 interventions in 3 treatment periods.

A.4.1

Sponsor's protocol code number

CV013-020

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1187-2123

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	Bristol-Myers Squibb International Corporation
B.1.3.4	Country	Belgium
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	Bristol-Myers Squibb International Corporation
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bristol-Myers Squibb International Corporation
B.5.2	Functional name of contact point	GCT-SU
B.5.3	Address:
B.5.3.1	Street Address	Parc de l'Alliance - Avenue de Finlande, 4
B.5.3.2	Town/ city	Braine-l'Alleud
B.5.3.3	Post code	1420
B.5.3.4	Country	Belgium
B.5.6	E-mail	clinical.trials@bms.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	BMS-986231-01 for Injection, 240 mg/vial
D.3.2	Product code	BMS-986231
D.3.4	Pharmaceutical form	Powder for concentrate 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	HNO
D.3.9.1	CAS number	1620330-72-4
D.3.9.2	Current sponsor code	CV013-020
D.3.9.3	Other descriptive name	BMS986231
D.3.9.4	EV Substance Code	SUB182812
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	240
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	Solinitrina
D.2.1.1.2	Name of the Marketing Authorisation holder	Kern Pharma/ BBraun Medical SA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	nitroglycerin
D.3.2	Product code	nitroglycerin
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 use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GLYCERYL TRINITRATE
D.3.9.1	CAS number	C 01 DA
D.3.9.2	Current sponsor code	C 01 DA
D.3.9.3	Other descriptive name	GLYCERYL TRINITRATE
D.3.9.4	EV Substance Code	SUB13997MIG
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	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	Concentrate 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

Heart failure and impaired systolic function

E.1.1.1

Medical condition in easily understood language

Inability of the heart to pump sufficiently to maintain blood flow to meet the body's needs.

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10074631
E.1.2	Term	Systolic heart failure
E.1.2	System Organ Class	100000004849

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10019279
E.1.2	Term	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

Evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to placebo.

E.2.2

Secondary objectives of the trial

- Evaluate the effects of BMS-986231 on the left ventricular (LV) systolic function by stroke volume index (SVI) assessed by echocardiography compared to nitroglycerin (NTG).
- Evaluate the effects of BMS-986231 on selected other left ventricular systolic and diastolic indices compared to placebo and NTG

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed Written Informed Consent
a) Subjects will be required to provide a written informed consent.

2) Type of Participant and Target Disease Characteristics
a) Males and Females, ages 18 (or age of majority) or older
b) Heart failure with reduced ejection fraction (LVEF on echocardiogram of 40% or less)c) Stable guideline directed therapy for heart failure including oral diuretics, ACEi, ARBs, ARNi, MRAs , and β blockers as tolerated), with no dose changes of these medications in the past 2 weeks
d) Have screening values of NT pro-BNP ≥ 125 pg/mL (15 pmol/L) or BNP ≥ 35 pg/mL (10 pmol/L).
e) In sinus rhythm at the start of the infusion

3) Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment.
b) Women must not be breastfeeding
c) Women of childbearing potential (WOCBP) must agree to follow instructions for methods of contraception for 32 days after discontinuation (duration of study drug plus 30 days duration of one ovulatory cycle).
d) Males who are sexually active with WOCBP must agree to follow instructions for methods of contraception (Appendix 4) for total of 91 days after discontinuation (duration of study drug plus 90 days (duration of sperm turnover).
e) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, but still must undergo pregnancy testing as described in this section. Investigators shall counsel WOCBP, and male participants who are sexually active with
WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4 which have a failure rate of < 1% when used consistently and correctly.
Local laws and regulations may require use of alternative and/or additional contraception methods.

E.4

Principal exclusion criteria

1) Target Disease Exceptions
a) Systolic blood pressure (SBP) < 110 mm Hg at screening or pre-randomization
b) Heart rate < 50 beats per minute (bpm) or > 90 bpm at screening orpre-randomization
c) Permanent Atrial Fibrillation, Atrial Flutter or having Atrial Fibrillation, Atrial Flutter before start of the infusion
d) Permanent paced rhythm (VVI, DDD or BiV pacing)
e) NYHA Class IV symptoms of heart failure

2) Medical History and Concurrent Disease
a) Primary HF etiology attributable to either restrictive/obstructive cardiomyopathy, idiopathic hypertrophic or uncorrected severe valvular disease as defined by AHA/ACC/ESC criteria. (Note: A restrictive mitral inflow pattern is not exclusionary)
b) Pericardial tamponade or constrictive pericarditis
c) Large post-MI LV aneurisms
d) Intra-cardiac thrombus
e) Prior mitral valve repair, mitral or aortic prosthesis of any type.
f) LV assist device or prior heart transplant
g) Hospitalized for acute decompensated heart failure in the previous month
h) Hospitalized with acute coronary syndrome, coronary evascularization or acute myocardial infarction during the previous 90 days prior to screening
i) Have a history of a cerebral vascular accident (CVA or stroke) or of a transient ischemic attack (TIA) during the previous 90 days prior to screening
j) Considered clinically unstable for any condition
k) Serious comorbid non cardiovascular disease in which the life expectancy of the subject is < 3 months
l) Liver disease defined as history of cirrhosis with evidence of portal hypertension such as varices, or encephalopathy, or total bilirubin > 3 mg/dL (> 51 μmol/L) or significant elevation of liver enzymes (AST, ALT > 3 times the upper limit of normal)
m) Prior solid organ transplant

3) Prior/Concomitant Therapy
a) Treatment with oral phosphodiesterase type 5 (PDE5) inhibitor sildenafil, vardenafil or avanafil within 24 hours of study drug infusion or treated with tadalafil within 4 days of study drug infusion
b) Treatment with intravenous inotropic therapy (dobutamine, milrinone, leveosimendan) in the previous month or planned treatment in next 3 months.
c) Current treatment with chronic oral, transdermal or sublingual nitrates, except at the discretion of the investigator and treating
physician, nitrates could be temporarily interrupted. In which case, an
interruption of 3 days is required prior to start of study drug.

4) Physical and Laboratory Test Findings
a) Estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m2
b) Have persistent abnormal serum electrolytes not resolved between screening and start of
the study drug infusion, as defined by any of the following:
i) A sodium (Na+) concentration < 130 or >145 mEq/L (mmol/L)
ii) A potassium (K+) concentration < 3.2 or >5.5 mEq/L (mmol/L)
c) Have severe anemia, as documented by a hemoglobin < 9 g/dL (< 5.59 mmol/L)

5) Allergies and Adverse Drug Reaction
a) Any history of allergic reaction to BMS-986231, or its components, Captisol® or potassium acetate.
b) Allergic reactions to organic nitrates

6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note:
under certain specific circumstances a person who has been imprisoned
may be included or permitted to continue as a participant. Strict
conditions apply and Bristol-Myers Squibb's approval is required.
b) Participants who are compulsorily detained for treatment of either a
psychiatric or physical (e.g., infectious disease) illness
c) Participation in an investigational clinical drug study within 30 days or
5 elimination half-lives, (whichever is longer) prior to randomization.
d) Prior participation and treatment in a study using BMS-986231, CXL-
1427, or CXL 1020
e) Alcohol beverage consumption within 6 hours prior to randomization.
f) Low quality echocardiographic visualization windows and image
acquisition
g) Body weight < 45 kg or 140 kg
h) Known hypersensitivity or contra-indication to the intravenous
echocardiography contrast
agent, in the event contrast echocardiography is used.

E.5 End points

E.5.1

Primary end point(s)

Mean SVI derived from the velocity time integral at the left ventricular outflow tract (LVOT VTI) at the end of the 5-hours infusion of BMS-
986231, versus placebo.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the 5-hours infusion

E.5.2

Secondary end point(s)

- Mean SVI derived from LVOT VTI at the end of the 5-hours infusion of BMS-986231, versus NTG.
- Mean LVEF, computed by Simpson’s method at the end of the 5-hours infusion of BMS-986231, versus placebo and NTG.
- Mean cardiac power index at the end of the 5-hours infusion of BMS-986231, versus placebo and NTG.
- Mean Diastolic indices: E/A, annular e' velocity and E/e' ratio at the end of the 5-hours infusion of BMS-986231, versus placebo and NTG.
- Mean LV global longitudinal strain, computed using STE at the end of the 5-hours infusion of BMS-986231, versus placebo and NTG.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the 5-hours 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

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

nitroglycerin (Solinitrina)

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

Japan

Netherlands

United Kingdom

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

End of trial is defined as the last visit or scheduled procedure shown in Section 2, the Schedule of Activities, for the last participant.

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:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

At the end of the study, BMS will not continue to provide BMS supplied study treatment to participants/investigators unless BMS chooses to extend the study. The investigator should ensure that the participant receives appropriate standard of care to treat the condition under study.

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

2018-03-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-05-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-05-10

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