Clinical Trials Register

Summary
EudraCT Number:	2017-001621-41
Sponsor's Protocol Code Number:	AC-011-IT
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-04
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-001621-41

A.3

Full title of the trial

A phase III randomized study of doxycycline and tauroursodeoxycholic acid (Doxy/TUDCA) plus standard supportive therapy versus standard supportive therapy alone in cardiac amyloidosis caused by transthyretin

Studio clinico in aperto di fase III, randomizzato, per valutare l’efficacia di un trattamento con doxiciclina e acido taurodesossicolico (Doxy-TUDCA) in associazione alla terapia di supporto standard contro la sola terapia di supporto standard, in pazienti affetti da amiloidosi cardiaca da transtiretina.

A.3.1

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

Treatment with doxycycline and tauroursodeoxycholic acid (Doxy/TUDCA) plus standard supportive therapy in cardiac amyloidosis caused by transthyretin

Trattamento con con doxiciclina e acido taurodesossicolico (Doxy-TUDCA) in aggiunta alla terapia standard in pazienti affetti da amiloidosi cardiaca da transtiretina

A.3.2

Name or abbreviated title of the trial where available

AmY-DoT

A.4.1

Sponsor's protocol code number

AC-011-IT

A.5.4

Other Identifiers

Name:

Number:

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 I.R.C.C.S. POLICLINICO SAN MATTEO
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	Società Italiana per L'Amiloidosi ONLUS
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 IRCCS Policlinico San Matteo
B.5.2	Functional name of contact point	Centro per lo studio e la cura dell
B.5.3	Address:
B.5.3.1	Street Address	P.le Golgi 19
B.5.3.2	Town/ city	27100
B.5.3.3	Post code	Pavia
B.5.3.4	Country	Italy
B.5.4	Telephone number	0382502994
B.5.5	Fax number	0382502990
B.5.6	E-mail	segreteria.amiloidosi@smatteo.pv.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	BASSADO - 100 MG COMPRESSE 10 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Doxiciclina
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	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	DOXICICLINA
D.3.9.1	CAS number	564-25-0
D.3.9.2	Current sponsor code	NA
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	100
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.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	TAURO - 250 MG CAPSULE RIGIDE 20 CAPSULE
D.2.1.1.2	Name of the Marketing Authorisation holder	TEOFARMA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Acido tauroursodesossicolico
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Capsule, hard
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	ACIDO TAUROURSODESOSSICOLICO
D.3.9.1	CAS number	128-13-2
D.3.9.2	Current sponsor code	NA
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	250
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Cardiac amyloidosis caused by transthyretin

Amiloidosi cardiaca da transtiretina

E.1.1.1

Medical condition in easily understood language

Cardiac amyloidosis caused by transthyretin

Amiloidosi cardiaca causata da transtiretina

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	PT
E.1.2	Classification code	10007509
E.1.2	Term	Cardiac amyloidosis
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy (superiority) of Doxy/TUDCA in patients with cardiac ATTR
amyloidosis,

Valutare l'efficacia di Doxy/TUDCA nei pazienti con amiloidosi cardiaca da transtiretina.

E.2.2

Secondary objectives of the trial

-To compare overall survival at 18 and 30 months of patients receiving Doxy/TUDCA in addition to standard supportive therapy with that of patients receiving standard supportive therapy alone.
- To assess safety of Doxy/TUDCA by measuring the rate and grade of adverse events.
- To assess changes in biochemical, echocardiographic, and clinical markers of disease severity during and after treatment.
- To assess the impact of re-treatment with Doxy/TUDCA in patients who experience a major
cardiac event after Doxy/TUDCA.
- To assess discontinuation on biochemical, echocardiographic, and clinical markers of disease
severity.
- To assess the impact of treatment with Doxy/TUDCA in patients originally enrolled in the
control arm who experience a “major cardiac event” and are then given Doxy/TUDCA on biochemical, echocardiographic, and clinical markers of disease severity.

- confrontare la sopravvivenza globale a 18 e 30 mesi dei pazienti trattati Doxy/TUDCA in aggiunta alla terapia di supporto standard, rispetto ai
pazienti trattati unicamente con terapia di supporto standard.
- valutare la sicurezza di Doxy/TUDCA, misurando frequenza e grado degli eventi avversi.
- valutare i cambiamenti negli esami biochimici, nell’esame ecocardiografico, e nei marcatori clinici di gravità della malattia, durante e dopo il trattamento.
- valutare l'impatto del ri-trattamento con Doxy/TUDCA sugli esami biochimici, ecocardiografici e sui marker clinici di gravità della malattia nei pazienti che presentano un importante evento cardiaco dopo la sospensione di Doxy/TUDCA.
- valutare l'impatto della discontinuazione sugli esami biochimici, ecocardiografici e sui marker clinici della malattia.
- valutare l'impatto del trattamento con Doxy/TUDCA su marcatori biochimici, ecografici e clinici di gravità della malattia nei pazienti originariamente arruolati nel gruppo di contro

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Diagnosis of ATTRwt amyloidosis, or ATTRm p.Ile68Leu and p.Val122Ile;
- 18 years or older;
- cardiac involvement (mean left ventricular wall thickness >12 mm in the absence of other causes);
- history of occurrence of at least 1 event of symptomatic heart failure;
- stable diuretic dosage for at least 2 weeks before treatment initiation;
- agree to practice effective methods of contraception where necessary
- voluntary written consent

- diagnosi di amiloidosi ATTRwt, o ATTRm p.Ile68Leu e p.Val122Ile.
- età maggiore di 18 anni
- coinvolgimento cardiaco (spessore della parete ventricolare media >12 mm assenza di altre cause)
- storia di insorgenza di almeno un caso di insufficienza cardiaca sintomatica
- dosaggio diuretico stabile per almeno due settimane prima di iniziare il trattamento
- utilizzo di adeguato metodo contraccettivo, ove necessario
- consenso informato scritto

E.4

Principal exclusion criteria

- Non-ATTR amyloidosis
- pregnant or nursing women
- uncontrolled bacterial, viral, fungal, HIV, HBV, or HCV infection;
- presence of other active malignancy with
- known allergy to tetracycline;
- treatment with drugs potentially affecting doxycycline absorption
- significant acute gastrointestinal symptoms;
- active peptic ulceration and/or esophageal reflux disease

- amiloidosi non-ATTR
- donne in gravidanza o in allattamento
- infezione non controllata
- presenza di altri tumori maligni attivi
- allergia nota alle tetracicline
- trattamento con farmaci che potenzialmente influenzano l'assorbimento della doxiciclina
- sintomi gastrointestinali acuti significativi
- ulcera peptica attiva e/o malattia da reflusso esofageo

E.5 End points

E.5.1

Primary end point(s)

Major cardiac events

Eventi cardiaci maggiori

E.5.1.1

Timepoint(s) of evaluation of this end point

18 months

18 mesi

E.5.2

Secondary end point(s)

Overall survival; Adverse events equal or higher grade 3 (CTCAE v 5.0); Changes in BNP, NT-proBNP, cTnI, mLVW, EF, MCF, GLS, 6MWT

Sopravvivenza globale; Eventi avversi grado 3 o superiore (CTCAE v 5.0); Cambiamenti nei valori di BNP, NT-proBNP, cTnI, spessore mLVW, EF, MCF, GLS, 6MWT

E.5.2.1

Timepoint(s) of evaluation of this end point

18 and 30 months; At each visit; After 6, 12, 18 months during treatment and at 6, 12 months after the end of treatment

18 e 30 mesi; Ad ogni visita; A 6, 12 e 18 mesi durante il trattamento, e 6 e 12 mesi dopo la sospensione del trattamento rispetto al basale

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Terapia di supporto standard

Standard supportive therapy

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

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.1.1.1

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)

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

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

102

F.4.2

For a multinational trial

F.4.2.1

In the EEA

102

F.4.2.2

In the whole clinical trial

102

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)

Access to treatment with Doxy/TUDCA will be granted to experimental arm patients who experience a "major cardiac event" off-treatment during the follow-up period and to ontrol arm patients after they meet the primary endpoint.

L'accesso al trattamento con Doxy/TUDCA sarà concesso a pazienti randomizzati nel braccio sperimentale che presentano un evento cardiaco importante durante il periodo di follow-up “off-therapy” e ai pazienti randomizzati nel braccio di controllo dopo che abbiano raggiunto l'end-point primario.

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

2017-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-06-05

P. End of Trial
P.	End of Trial Status	Ongoing

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