Clinical Trials Register

Summary
EudraCT Number:	2015-005383-42
Sponsor's Protocol Code Number:	BREATH
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-01-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-005383-42

A.3

Full title of the trial

Use of buspiron in chemioreflex modulation and central apnea treatment in heart failure patients (BREATH: BuspiRon for chEmoreflex modulation and central Apnea treatment in Heart failure patients). Phase II, monocentric, cross-over, duble dummy, randomized and controlled, pilot study.

Utilizzo del buspirone nella modulazione del chemoriflesso e nel trattamento delle apnee in pazienti con scompenso cardiaco (BREATH: BuspiRon for chEmoreflex modulation and central Apnea treatment in Heart failure patients) Studio clinico pilota di fase II, monocentrico, cross-over, in doppio cieco, randomizzato e controllato.

A.3.1

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

BuspiRon for chEmoreflex modulation and central Apnea treatment in Heart failure patients

Utilizzo del buspirone nella modulazione del chemoriflesso e nel trattamento delle apnee in pazienti con scompenso cardiaco

A.3.2

Name or abbreviated title of the trial where available

BREATH

A.4.1

Sponsor's protocol code number

BREATH

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	FONDAZIONE TOSCANA GABRIELE MONASTERIO
B.1.3.4	Country	Italy
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	Fondazione Toscana Gabreiele Monasterio
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Toscana Gabriele Monasterio
B.5.2	Functional name of contact point	UOC Medicina Cardiovascolare
B.5.3	Address:
B.5.3.1	Street Address	via Moruzzi 1
B.5.3.2	Town/ city	Pisa
B.5.3.3	Post code	56126
B.5.3.4	Country	Italy
B.5.4	Telephone number	0585493507
B.5.5	Fax number	0585493508
B.5.6	E-mail	farmacisti@ftgm.it

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	Anxut 5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Eisai
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BUSPIRONE
D.3.9.2	Current sponsor code	BUSPIRONE
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

patient with central apneas syndrome and heart failure

pazienti affetti da scompenso cardiaco e sindrome delle apnee centrali del sonno

E.1.1.1

Medical condition in easily understood language

patient with central apneas syndrome and heart failure

pazienti affetti da scompenso cardiaco e sindrome delle apnee centrali del sonno

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	10011949
E.1.2	Term	Decompensation cardiac
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	HLT
E.1.2	Classification code	10040978
E.1.2	Term	Sleep apnoeas
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluation of buspiron effects on chemoceptive sensitivity to carbon dioxide (CO2) in heart
failure patients with CO2 hypersensitivity

valutare gli effetti del buspirone sulla sensibilità chemocettiva centrale all’anidride carbonica
(CO2) in pazienti con scompenso cardiaco ed ipersensibilità chemocettiva alla CO2

E.2.2

Secondary objectives of the trial

Evaluation of buspiron effects on the same patients on: 1) Nocturnal apneas; 2) Neurohormonal balance, with a specific focus on the adrenergic axis; 3) Sympathovagal balance, evaluated by means of the Holter ECG; 4) Exercise capacity, evaluated by means of the cardiopulmonary exercise test.

Valutare gli effetti del buspirone negli stessi pazienti su: 1) apnee notturne; 2) assetto neurormonale, con particolare attenzione all’asse adrenergico; 3) bilancia simpatovagale, valutata mediante Holter ECG; 4) capacità di esercizio, valutata mediante test cardiopolmonare

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age between 18 and 80 years; 2) Heart failure (diagnosed according to Framingham criteria) with a left ventricular dysfunction (ejection fraction-EF <50%), New York Heart Association (NYHA) classes I-III; 3) Chemoreflex activation to hypercapnia (cut point ≥ 0.79); 4) Central apneas at the cardiorespiratory monitoring, with an AHI≥ 15 events/hour (moderatesevere central apneas); 5) Capability and possibility to follow and complete the study; 6) Informed consent signature.

1) età compresa tra i 18 e i 80 anni; 2) scompenso cardiaco (diagnosi in accordo ai criteri di Framingham) legato ad una disfunzione
sistolica del ventricolo sinistro (frazione di eiezione–FE <50%) classe NYHA I-III (classificazione New York Heart Association); 3) attivazione del chemoriflesso all’ipercapnia (cut-point ≥0.79); 4) presenza di apnee centrali al monitoraggio cardiorespiratorio, con un AHI≥ 15 eventi/ora (apnee centrali di grado moderato-severo); 5) capacità e possibilità di seguire e completare lo studio; 6) firma del consenso informato;

E.4

Principal exclusion criteria

1) Participation in the previous 3 months to other clinical studies;
2) Pregnant, breast-feeding women or fertile women that do not follow and adequate contraception (every woman must consent to abstinence from sexual intercourse, or adopt any two of the following contraception measures considered efficacious as: bilateral tube ligation, male sterilization, use of hormonal contraceptives that inhibit ovulation, copper intrauterine devices; every barrier device must be used together with a spermicide cream);
3) Recent acute heart failure or acute coronary syndrome (in the last 3 months);
4) Chronic severe renal insufficiency (creatinin clearance <20 ml/min/1.72 m2);
5) Chronic obstructive pulmonary disease (FEV1/FVC<70% and FEV1< 70%);
6) Hepatic insufficiency (transaminases AST/ALT > 100 U/L and/or gamma GT > 150 U/L);
7) Major unstable psychiatric disorders and/or use of psychoactive agents and agents that can influence respiratory drive (ATC: N02A (opiates), N02CC (serotonin agonists), N03 (antiepileptic agents), N04A (anticholinergic agents), N04B (dopaminergic agents), N05 (psycholeptic agents), N06 (antidepressants), S01EC01 (acetazolamide), R03DA (xanthine),
R03DB (xanthine and adrenergic agents);
8) Concomitant use of drugs that inhibit or induce hepatic metabolism, in light of buspiron hepatic
metabolism;
9) History of drug or alcohol dependence;
10) Administration of any experimental drug within 30 days of the enrollment in the present study;
11) Active malignancies;
12) Known or suspected allergy to the drugs subjected to investigation or to one or more of the excipients;
13) Lactose intolerance;
14) Incapability to sign the informed consent form;
15) Closed angle glaucoma;
16) Miastenia gravis;
17) Hereditary galactose intolerance, lactase deficieny or glucose-galactose malabsorption;
18) Any other condition or disease that, to the investigator judgment, may interfere with the present study.

1) partecipazione ad altri studi clinici nei 3 mesi precedenti;
2) donne in stato di gravidanza, in allattamento o in età fertile che non seguano adeguata contraccezione (la donna deve acconsentire all’astinenza dall’intercourse eterosessuale o adoperare almeno due misure contraccettive considerate efficaci quali: legatura bilaterale delle tube, sterilizzazione maschile, utilizzo di contraccettivi ormonali che inibiscono l’ovulazione, device intrauterini che rilasciano ormoni, device intrauterini in rame; tutti i device di barriera devono essere utilizzati in combinazione con una crema spermicida);
3) recente scompenso acuto o sindrome coronarica acuta (ultimi 3 mesi);
4) insufficienza renale severa (clearance della creatinina <20 ml/min/1.72 m2);
5) presenza di broncopneumopatia cronica ostruttiva di grado moderato o severo (FEV1/FVC<70% del predetto e FEV1< 70%);
6) insufficienza epatica (transaminasi AST/ALT > 100 U/L e/o gamma GT > 150 U/L);
7) disordini psichiatrici maggiori instabili o trattamento con farmaci psicoattivi o in grado di agire sul drive respiratorio (ATC: N02A (oppiodi), N02CC (agonisti serotonina), N03 (antiepilettici), N04A (anticolinergici), N04B (agenti dopaminergici), N05 (psicolettici), N06 (antidepressivi), S01EC01 (acetazolamide), R03DA (xantine), R03DB (xantine e adrenergici);
8) utilizzo concomitante di farmaci che inibiscono o inducono il metabolismo epatico dei farmaci, in relazione al metabolismo epatico del buspirone;
9) storia di dipendenze da droghe o alcool;
10) somministrazione di qualsiasi farmaco sperimentale entro 30 giorni dal previsto arruolamento nel presente studio;
11) neoplasie in fase attiva;
12) allergia nota o sospetta al farmaco in studio o ad uno degli eccipienti;
13) intolleranza al lattosio;
14) incapacità a fornire il consenso informato;
15) glaucoma ad angolo stretto;
16) miastenia grave;
17) problemi ereditari di intolleranza al galattosio, deficit di lattasi o malassorbimento di glucosio-galattosio;
18) ogni altra condizione o malattia che a giudizio dello sperimentatore possa interferire con lo svolgimento dello studio.

E.5 End points

E.5.1

Primary end point(s)

A difference of 0.5 of the hypercapnic ventilatory response (HCVR) compared to the
placebo, assessed with the rebreathing technique, evaluated at day 1 and repeated at day 8,
15 and 22. Briefly, the patient breaths into a closed circuit, with progressive increase of CO2,
while stabilizing FiO2 by means of external oxygen flow. Carbon dioxide sensitivity is
expressed as the linear regression slope between ventilation and the end tidal CO2 (et-CO2)
(additional technical details in the protocol)

Una differenza della risposta chemocettiva all’ipercapnia o HCVR (hypercapnic ventilatory response) di 0.5 rispetto al placebo mediante tecnica del rebreathing, valutata al giorno 1 e ripetuta al giorno 8, al giorno 15 e al giorno 22. In breve il paziente verrà fatto respirare all’interno di un circuito chiuso, con
progressivo incremento dei valori di anidride carbonica, stabilizzando i valori di ossiemia mediante
flusso esterno di ossigeno. La sensibilità chemocettiva all’anidride carbonica verrà espressa come
regressione lineare dell’incremento ventilatorio associato all’incremento di anidride carbonica.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 1, 8, 15 and 22.

Giorni 1, 8, 15 e 22

E.5.2

Secondary end point(s)

Evaluation of the effects of the drug on exercise performance with the cardiopulmonary stress test by means of a cycle-ergometer.

Valutazione degli effetti del farmaco sulla performance al test cardiopolmonare mediante test al cicloergometro.

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluation at day 0 and repeated at day 7 and day 21.

Rilevazione effettuata il giorno 0 e ripetuta il
giorno 7 e il giorno 21.

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

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

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)

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

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

studio pilota

pilot study

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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

Number of subjects for this age range:

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:

F.1.3

Elderly (>=65 years)

Yes

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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)

None

Nessuno

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

2016-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-07

P. End of Trial
P.	End of Trial Status	Completed

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