Clinical Trials Register

Summary
EudraCT Number:	2011-001845-34
Sponsor's Protocol Code Number:	AMBIHOW
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:	2012-03-02
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

2011-001845-34

A.3

Full title of the trial

LIPOSOMAL AMPHOTERICIN B (AMBISOME) 10 mg/kg once a week for 10 weeks as maintenance antifungal therapy for Proven/Probable Invasive Fungal Infection in hematologic patients with Acute Myeloid Leukaemia and/or in Allogeneic Hematopoietic Stem Cell Transplant recipients.

AMFOTERICINA B liposomiale (Ambisome ) 10 mg/kg una volta alla settimana per 10 settimane come terapia di mantenimento per infezioni fungine invasive certe/probabilili in pazienti ematologici con leucemia mieloide acuta e/o in pazienti con trapianto di cellule staminali allogeniche

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

AMBIHOW

A.4.1

Sponsor's protocol code number

AMBIHOW

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	AZIENDA OSPEDALIERA DI BOLOGNA POLICLINICO S. ORSOLA M. MALPIGHI
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	GILEAD
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	AOU di Bologna, Policlinico S.Orsola-Malpighi
B.5.2	Functional name of contact point	U.O. Malattie Infettive Prof. Viale
B.5.3	Address:
B.5.3.1	Street Address	Via Albertoni 15
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40138
B.5.3.4	Country	Italy
B.5.4	Telephone number	051/6363353
B.5.5	Fax number	051/343500
B.5.6	E-mail	pierluigi.viale@unibo.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	AMBISOME*INFUS 10FL LIOF 50MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES Srl
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.3.4	Pharmaceutical form	Powder 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	AMPHOTERICINE B, LIPOSOME
D.3.9.1	CAS number	8000078822
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
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.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	AMBISOME*INFUS 10FL LIOF 50MG
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES Srl
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.3.4	Pharmaceutical form	Powder 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	AMPHOTERICINE B, LIPOSOME
D.3.9.1	CAS number	8000078822
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Proven/Probable Invasive Fungal Infection in hematologic patients with Acute Myeloid Leukaemia and/or in Allogeneic Hematopoietic Stem Cell Transplant recipients.

infezioni fungine invasive certe/probabilili in pazienti ematologici con leucemia mieloide acuta e/o in pazienti con trapianto di cellule staminali allogeniche

E.1.1.1

Medical condition in easily understood language

Proven/Probable Invasive Fungal Infection in hematologic patients with Acute Myeloid Leukaemia and/or in Allogeneic Hematopoietic Stem Cell Transplant recipients.

infezioni fungine invasive certe/probabilili in pazienti ematologici con leucemia mieloide acuta e/o in pazienti con trapianto di cellule staminali allogeniche

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

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	10061730
E.1.2	Term	Bone marrow transplant
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10028484
E.1.2	Term	Mycoses fungoides
E.1.2	System Organ Class	10005329 - Blood and lymphatic system 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

The main objective of the study is to assess the efficacy of 10 administrations of L-AmB 10 mg/kg once a week as maintenance antifungal therapy after 14 days of standard therapy with L-AmB 3 mg/kg once a day in hematologic patients in treatment for Acute Myeloid Leukemia and Allogeneic-HSCT recipients with a diagnosis of Probable/Proven IFI with complete, partial response or stable disease, in terms of complete partial or response at 10 weeks from start of maintenance therapy (i.e. overall treatment duration 12 weeks).

L'obiettivo principale dello studio è di valutare l'efficacia di 10 somministrazioni di L-AMB 10 mg / kg una volta alla settimana come terapia di mantenimento antifungina dopo 14 giorni di terapia standard con L-AMB 3 mg / kg una volta al giorno nei pazienti ematologici in trattamento per leucemia mieloide acuta, riceventi trapianto allogenico con una diagnosi di IFI probabile / provata con risposta completa, parziale o stabilità di malattia, in termini di totale o parziale risposta a 10 settimane dall'inizio della terapia di mantenimento (cioè la durata del trattamento complessivo del 12 settimane)

E.2.2

Secondary objectives of the trial

• To estimate FFS and OS at 10 and 22 weeks (i.e. 12 and 24 weeks from treatment initiation);
• To estimate the proportion of patients with adverse event, globally and for each adverse event;
• To calculate the Daily Dose Dispensed (DDD) for L-AmB in this therapeutic regimen;
• To calculate hospital stay duration

• Stimare Free-Fungal Survival (FFS) e Overall Survival (OS) a 10 e 22 settimane (cioè 12 e 24 settimane a partire dall'inizio del trattamento);
• Stimare la proporzione di pazienti con eventi avversi a livello globale e per ogni evento avverso;
• Calcolare la Daily Dose Dispensed (DDD) per L-AMB in questo regime terapeutico;
• Calcolare la durata di permanenza in ospedale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion  Patients with diagnosis of AML in treatment with high dose chemotherapy or undergoing Allogeneic-HSCT, with a life expectancy superior to 3 months
 Age superior or egual to 18 years
 Probable or Proven IA according with EORTC criteria21, treated with L-AMB 3 mg/kg/die for 14 days
 Favorable overall clinical response reached, defined by the criteria described in Table 2; also, patients with stable response after 14 days of treatment will be included
Note: response assessment is usually made later than 14 days from start of treatment, i.e. at the time of potential enrollment in the present trial. We therefore think that patient stable at this time-point do not represent (yet) a clinical failure and therefore can be included in the study.
 Creatinine clearance superior to 50 ml/min
 Serum potassium superior to 3.5 mg/mL
 AST / ALT inferor to 5 times upper limit of normal
 Willingness to provide informed consent

 Pazienti con diagnosi di LMA in trattamento con chemioterapia ad alte dosi o sottoposti a a trapianto di midollo allo genico, con una aspettativa di vita superiore a tre mesi
 Età maggiore o uguale 18 anni
 IA Probabile o Provata secondo i criteri EORTC21, trattata con L-AMB 3 mg/kg/die per 14 giorni
 Raggiungimento di globale risposta clinica favorevole, definita dai criteri descritti nella tabella 2; saranno inlclusi anche i pazienti con risposta stabile dopo i 14 giorni di terapia
Nota: La valutazione della risposta è usualmente fatta più tardi dei 14 giorni di terapia dall’inizio del trattamento, ossia al momento del potenziale arruolamento nel presente studio. Riteniamo quindi che il paziente stabile a questo punto non rappresenti (ancora) un fallimento clinico e quindi che possa essere incluso nello studio.
 Clearance Creatinina maggiore a 50 ml/min
 Potassio sierico maggiore a 3.5 mg/mL
 AST / ALT inferiore a 5 volte oltre i limiti di normalità
 Capacità di fornire consenso informato

E.4

Principal exclusion criteria

 Diagnosis of IFI other than IA
 Life expectancy <30 days
 Participation in other experimental studies at the time of consent
 Ongoing pregnancy

 Diagnosi di IFI oltre che IA
 Aspettativa di vita inferiore a 30 giorni
 Participazione in altri studi sperimentali al momento del consenso
 Gravidanza

E.5 End points

E.5.1

Primary end point(s)

Efficacy of 10 administrations of L-AmB 10 mg/kg once a week as maintenance antifungal therapy after 14 days of standard therapy with L-AmB 3 mg/kg once a day in hematologic patients in treatment for Acute Myeloid Leukemia and Allogeneic-HSCT recipients with a diagnosis of Probable/Proven IFI with complete, partial response or stable disease, in terms of complete partial or response at 10 weeks from start of maintenance therapy

E.5.1.1

Timepoint(s) of evaluation of this end point

12 weeks

12 settimane (di cui 10 settimane terapia di mantenimento)

E.5.2

Secondary end point(s)

Stimare Free-Fungal Survival (FFS) e Overall Survival (OS) a 10 e 22 settimane (cioè 12 e 24 settimane a partire dall'inizio del trattamento);
• Stimare la proporzione di pazienti con eventi avversi a livello globale e per ogni evento avverso;
• Calcolare la Daily Dose Dispensed (DDD) per L-AMB in questo regime terapeutico;
• Calcolare la durata di permanenza in ospedale

E.5.2.1

Timepoint(s) of evaluation of this end point

24 weeks

24 settimane dall'inizio di trattamento

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

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

E.8.1.1

Randomised