Clinical Trials Register

Summary
EudraCT Number:	2017-002210-31
Sponsor's Protocol Code Number:	AC-012-EU
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:	2020-12-15
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-002210-31

A.3

Full title of the trial

A randomized phase II/III trial of doxycycline vs. standard supportive therapy in
newly-diagnosed cardiac AL amyloidosis patients undergoing bortezomib-based therapy

Studio clinico randomizzato di fase II/III volto a confrontare una terapia a base di doxiciclina con una terapia di supporto standard, in pazienti di nuova diagnosi di amiloidosi AL a coinvolgimento cardiaco, per i quali ¿ in programma una terapia a
base di bortezomib.

A.3.1

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

Study to compare doxycycline versus antibiotic standard therapy, to be added to bortezomib, in newly-diagnosed cardiac AL amyloidosis

Studio per il confronto tra doxiciclina versus terapia antibiotica standard in aggiunta a bortezomib in pazienti con nuova diagnosi di amiloidosi AL a coinvolgimento cardiaco

A.3.2

Name or abbreviated title of the trial where available

Redox

A.4.1

Sponsor's protocol code number

AC-012-EU

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	Ministero della Salute
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 di Pavia
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	Pavia
B.5.3.3	Post code	27100
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.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 AL amyloidosis

AL amiloidosi con coinvolgimento cardiaco

E.1.1.1

Medical condition in easily understood language

Cardiac AL amyloidosis

AL amiloidosi con coinvolgimento cardiaco

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

Evaluation of survival after 12 months

Valutazione della sopravvivenza dopo 12 mesi

E.2.2

Secondary objectives of the trial

- safety, i.e. rate of severe (CTCAE v5.0) grade 3 or greater adverse events)
- rate of infective adverse events of any grade
- cardiac response at 2, 4, 6 and 12 months
- hematologic response at 2, 4, 6 and 12 months
- renal response at 2, 4, 6 and 12 months

- Profilo di sicurezza, i.e. percentuale di eventi avversi di grado 3 o superiore (CTCAE v5.0)
- numero e gravit¿ degli eventi avversi registrati
- risposta cardiaca a 2, 4, 6 e 12 mesi
- risposta ematologica a 2, 4, 6 e 12 mesi
- risposta renale a 2, 4, 6 e 12 mesi

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age = 18.
2. newly-diagnosed AL amyloidosis.
3. Confirmed diagnoses of AL amyloidosis by the following:
a) histochemical diagnoses of AL amyloidosis determined by polarizing light microscopy of green birefringent material in Congo red stained issue
specimens OR characteristic electron microscopy appearance
AND
b) Confirmatory electron microscopy immunohistochemistry OR mass spectroscopy of AL amyloidosis. Confirmation of amyloid type can be omitted in patients with a clear-cut clinical evidence of AL amyloidosis (e.g. cardiac and renal involvement, soft tissue involvement) in the presence of a monoclonal component.
4. Cardiac involvement grade II/IIIa
5. Planned bortezomib-based therapy.
6. Total bilirubin <1.5 × upper reference limit (url), patients with Gilbert disease who have a total bilirubin, predominantly unconjugated >1.5 × url without any other liver function test abnormalities are still eligible.
7. Alkaline phosphatase <5 × url.
8. Alanine aminotransferase <3 × url.
9. Systolic blood pressure 90-180 mmHg.
10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy
test within 14 days prior to the first administration of study drug and perform a pregnancy test every 4 weeks to rule out pregnancy, they must agree to use highly effective physician-approved contraception from 30 days prior to the first study drug administration to 90 days following the last study drug administration. Acceptable methods of contraception are: hormonal contraceptive, diaphragm with spermicide, condom with spermicide or abstinence for the duration of the study.
11. Males must be surgically sterile or must agree to use highly effective physicianapproved
contraception from 30 days prior to the first study drug administration to 90 days following the last study drug administration.
12. Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures.

1. Età pari o superiore a 18 anni
2. Diagnosi recente di amiloidosi AL
3. Diagnosi confermata di amiloidosi AL in base a quanto segue:
a.Diagnosi istochimica di amiloidosi determinata mediante microscopia a luce polarizzata di materiale birifrangente verde in campioni di tessuto colorati con rosso Congo O aspetto caratteristico al microscopio elettronico
E
b. Immunoistochimica O spettroscopia di massa. La conferma del tipo di amiloide può essere omessa in pazienti con una evidenza clinica di amiloidosi AL in presenza di componente monoclonale.
4. Coinvolgimento cardiaco stadio II/IIIa
5. Programmata terapia a base di bortezomib
6. Bilirubina totale <1.5 × url, I pazienti con sindrome di Gilbert che presentano un livello di bilirubina totale, in predominanza non coniugata >1.5 × url, in assenza di altre anomalie ai test di funzionalità epatica, sono potenzialmente eligibili
7. Fosfatasi alcalina <5 × url
8. Alanina aminotrasferasi <3 × url
9. Pressione arteriosa sistolica 90-180 mmHg
10. Le pazienti in età fertile (WOCBP) devono presentare un test di gravidanza negativo nei 14 giorni prima della prima somministrazione del
farmaco dello studio ed effettuare un test di gravidanza su siero ogni 4 settimane. Devono accettare di utilizzare un metodo contraccettivo approvato dal medico a partire da 30 giorni prima della prima somministrazione fino a 90 giorni dopo l'ultima somministrazione del farmaco dello studio. I metodi di contraccezione accettati sono: contraccettivi ormonali, diaframma con utilizzo di spermicida, condom con utilizzo di spermicida o astinenza per tutta la durata dello studio.
11. I pazienti di sesso maschile devono essere chirurgicamente sterili o devono accettare di utilizzare un metodo contraccettivo approvato dal
medico a partire da 30 giorni prima della prima somministrazione fino a 90 giorni dopo l'ultima somministrazione del farmaco dello studio
12. Capacità di comprendere e disponibilità a firmare un modulo di consenso informato prima di avviare qualsiasi procedura dello studio

E.4

Principal exclusion criteria

1. Non-AL amyloidosis.
2. Stage IIIb cardiac involvement
3. Previous treatment for AL amyloidosis.
4. Clinically overt multiple myeloma with lytic bone lesions.
5. Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject’s ability to safely receive treatment or complete study
assessments.
6. Patients with uncontrolled infection or active malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I cancer from which the patient is currently in complete
remission, or any other cancer from which the patient has been disease-free for 5
years.
7. Known HIV positive.
8. Pregnant or nursing women.
9. Known hypersensitivity to doxycycline, bortezomib, boron, or mannitol.
10. Treatment with drugs potentially affecting doxycycline absorption.
11. Significant acute gastrointestinal symptoms.
12. Active peptic ulceration and/or esophageal reflux disease.
13. Patients with serious medical or psychiatric illness likely to interfere with participation
in this clinical study.
14. Contraindication to bortezomib based therapy

1. Amiloidosi non-AL
2. Coinvolgimento cardiaco allo stadio IIIb
3. Pazienti già trattati per amiloidosi AL
4. Mieloma multiplo clinicamente conclamato con lesioni ossee litiche
5. Ipotensione ortostatica sintomatica che secondo il giudizio medico dello sperimentatore potrebbe interferire con la capacità del paziente di sottoporsi in modo sicuro al trattamento o completare gli esami dello studio
6. Infezioni non controllate o malattie proliferative in fase attiva ad eccezione di tumore della pelle a cellule basali e squamose o cancro cervicale in situ
adeguatamente trattati, cancro allo stadio I adeguatamente trattato da cui il paziente è attualmente in fase di remissione completa o qualsiasi altro cancro da cui il paziente è libero da 5 anni
7. Positività HIV nota
8. Donne in gravidanza o che allattano
9. Ipersensibilità alla doxiciclina, al bortezomib, boro o mannitolo
10. Trattamento con farmaci in grado di modificare l’assorbimento della doxiciclina
11. Sintomi gastrointestinali acuti significativi
12. Ulcera peptidica attiva e/o presenza di reflusso esofageo
13. Pazienti con patologie mediche o psichiatriche che otrebbero interferire con la partecipazione allo studio.
14. Controindicazioni alla terapia a base di bortezomib

E.5 End points

E.5.1

Primary end point(s)

Survival

Sopravvivenza

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 mesi

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

2, 4, 6 and 12 months

2, 4, 6 e 12 mesi

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)

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

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

Profilassi antibiotica 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

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.8.6 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

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

120

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)

Standard supportive therapy

Terapia di supporto standard

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

2018-01-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-31

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials