Clinical Trials Register

Summary
EudraCT Number:	2016-002335-14
Sponsor's Protocol Code Number:	LAMBDA
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:	2020-11-04
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

2016-002335-14

A.3

Full title of the trial

A ß-d-glucan guided antifungal stewardship strategy for the management of patients with severe abdominal sepsis. A multicenter interventional explorative study with a pharmadynamic/pharmachokinetic substudy entitled:

“A Pilot substudy of Liposomal Amphotericin B Pharmacodynamics in Patients with Abdominal Sepsis” conducted only in the coordinating center

Strategia di gestione antimicotica guidata dal ß -d-glucano per pazienti con sepsi addominale grave. Studio interventistico multicentrico esplorativo con sottostudio di farmacocinetica/farmacodinamica intitolato:

“Sottostudio pilota di farmacodinamica di amfotericina B liposomiale in pazienti con sepsi addominale” che verrà condotto solo nel centro coordinatore

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

LAMBDA

A.4.1

Sponsor's protocol code number

LAMBDA

A.5.4

Other Identifiers

Name:

LAMBDA

Number:

LAMBDA

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	AOU DI BOLOGNA POLICLINICO S.ORSOLA-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
B.5.2	Functional name of contact point	U.O. Malattie Infattive
B.5.3	Address:
B.5.3.1	Street Address	Via Massarenti 9
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	0512143353
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 - 50 MG POLVERE PER SOLUZIONE PER INFUSIONE 10 FLACONCINI
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES 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	AmBisome
D.3.2	Product code	[AmBisome]
D.3.4	Pharmaceutical form	Powder 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	AMFOTERICINA B
D.3.9.2	Current sponsor code	amfotericina B
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with severe sepsis or septic shock

Pazienti con patologia chirurgica addominale severa; Pazienti con sepsi grave o shock settico

E.1.1.1

Medical condition in easily understood language

Patients with severe sepsis or septic shock

Pazienti con patologia chirurgica addominale severa; Pazienti con sepsi grave o shock settico

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	23.1
E.1.2	Level	PT
E.1.2	Classification code	10066593
E.1.2	Term	Post procedural sepsis
E.1.2	System Organ Class	10021881 - Infections and infestations

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	10058040
E.1.2	Term	Abdominal sepsis
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

With this study we would evaluate the safety of pre-emptive therapy with LamB 5 mg/kg in the first 24h of treatment followed by LamB 3 mg/kg starting from the third day in patients with predefined high risk for IC/IAC.

Obiettivo principale: Stabilire la sicurezza della terapia con LAmB 5 mg/kg nelle prime 24 ore di trattamento seguita da LAmB 3 mg/kg a partire dal 3 giorno nei pazienti con sospetta o confermata cadidiasi intraddominale invasiva (IAC).

E.2.2

Secondary objectives of the trial

1. To evaluate the cost-effectiveness of the use of BG in the management of antifungal therapy in patients with a severe surgical abdominal disease and severe sepsis or septic shock.
2. To assess the accuracy of BG for diagnosing IC/IAC in patients with severe abdominal surgical disease and severe sepsis or septic shock.
3. To investigate the outcome in terms of time to clinical stability, length of ICU and/or hospital stay, and rate of in-hospital mortality of the overall study cohort patients and in patients with IAC

(i) Stabilire il rapporto cost-efficacia dell’utilizzo del Beta-D-glucano nella gestione della terapia antifungina in pazienti con IAC;
(ii) Stabilire l’accuratezza del BD glucano nella diagnosi della IAC in pazienti con patologia addominale severa.
(iii) Stabilire l’outcome, la durata della degenza e la mortalità nei pazienti arruolati nello studio.
(v) stabilire il grado penetrazione tissutale di LamB e l’attività farmacodinamica nei pazienti con IAC (sottostudio di farmacocinetica/farmacodinamica condotto solo nel centro coordinatore)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Title:
A Pilot Substudy of Liposomal Amphotericin B Pharmacodynamics in Patients with Abdominal Sepsis” conducted only in the coordinating center

version 1.0 (14 june 2016)

Substudy is described in protocolo Lambda, sections: 12/3/14/15/

Substudy objective:
To assess pharmacokinetics and pharmacodynamic activity of a 5 mg/kg LamB dose during the first 24 hours in a subset of 14 patients (substudy that will be conducted only in the coordinating center)

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Titolo:
Sottotudio pilota di farmacodinamica di amfotericina B liposomiale in pazienti con sepsi addominale” che verrà condotto solo nel centro coordinatore

versione: 1.0 (14 giugno 2016);

Sottostudio è descritto nel documento Protocollo Lambda , capitoli 12/3/14/15/

Obiettivo di sottostudio:
stabilire il grado penetrazione tissutale di LamB e l’attività farmacodinamica nei pazienti con IAC (sottostudio di farmacocinetica/farmacodinamica condotto solo nel centro coordinatore)

E.3

Principal inclusion criteria

Inclusion criteria

1. All adult (= 18 years) patients
2. Patients with a severe surgical abdominal disease (SAD) defined as post-operative peritonitis, recurrent gastrointestinal perforation, post-operative hepatobiliary and pancreatic disorders, intra-abdominal abscess and anastomotic leak
3. Patients with severe sepsis or septic shock;
4. Signed informed consent

Criteri di inclusione:
i) età >18 anni;
ii)Pazienti con patologia chirurgica addominale severa;
iii)Pazienti con sepsi grave o shock settico ;
iv)Firma del consenso informato

E.4

Principal exclusion criteria

Exclusion criteria

1. Patients with documented history of hypersensitivity or allergic reaction to liposomial amphotericin B
2. Pregnancy, lactation or patients at risk for pregnancy: premenopausal or postmenopausal woman within 12 months of last menses without negative pregnancy test or not committing to adequate birth control (e.g., oral contraceptive, two methods of barrier birth control). Diagnosis of pregnancy will be done using quantitative blood ß-HCG test.
3. Neutropenia > grade 2 defined as absolute neutrophils count = 1000/mmc
4. Concomitant treatment with cyclosporine, aminoglycosides and pentamidine

Criteri di esclusione:
i) Anamnesi documentata di ipersensibilità o reazione allergica ad amfotericina B; ii) gravidanza, allattamento o soggetto potenzialmente a rischio di gravidanza (mancato uso di contraccettivi orali o almeno due barriere fisiche al concepimento in soggetto in età fertile o con almeno un ciclo mestruale negli 12 mesi; test di gravidanza: beta-HCG test) iii) neutropenia superiore al grado 2 definita come conta di neutrofili = 1000/mmc; iv) utilizzo concomitante di ciclosporina, aminoglicosidi e pentamidina

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoint:

Safety will be assessed according to the incidence of grade 3 to 4 adverse events (AEs) based on the Common Toxicity Criteria (CTC) classification, reported as definitely, possibly, or probably related to the study drug. The incidence of adverse events will be investigated from the initiation of the study drug until to 30 days after the study drug discontinuation.
An iterim analysis will be performed after the enrollment of 19 patients. Only a rate of 10% of AEs will be acceptable (see sample size and iterim analysis section)

L’endpoint primario dello studio è la sicurezza che verrà valutata attraverso l’incidenza degli eventi avversi di grado 3 e 4 secondo la classificazione common toxicity criteria (CTC). Il monitoraggio degli avventi avversi avverà dall’inizio del trattamento e proseguirà per 30 giorni dopo la sospensione

E.5.1.1

Timepoint(s) of evaluation of this end point

2 months (maximum 28 days of treatment and 30 days of follow-up after the end of treatment)

2 mesi (massimo 28 giorni di trattamento e follow-up di 30 giorni dopo il termine di terapia)

E.5.2

Secondary end point(s)

1. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of BG for diagnosing IC/IAC, established according to clinical and microbiological criteria, will be analyzed.
2. The time from severe sepsis or septic shock onset to clinical stability, the days of ICU and/or hospital stay and in-hospital all-cause mortality will be evaluated for all the enrolled patients and for patients with confirmed IC/IAC

6.2 Secondary Endpoints:

- il tempo di stabilizzazione clinica dall’inizio della terapia antimicrobica, la mortalità a 30 giorni dalla diagnosi di SAD e la durata di degenza e di trattamento antifungino nei pazienti arruolati;
-la sensibilità, la specifità, valore, predittivo positivo e negativo del BG nella diagnosi di IC/IAC

E.5.2.1

Timepoint(s) of evaluation of this end point

2 months (maximum 28 days of treatment and 30 days of follow-up after the end of treatment)

2 mesi (massimo 28 giorni di trattamento e follow-up di 30 giorni dopo il termine di terapia)

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

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Studio NON controllato: sezione E.8.1: problema OsSC AIFA

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

Studio NON controllato: sezione E.8.1: problema OsSC AIFA

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

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)

Usual patient care

Normale percorso assistenziale

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

2018-12-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-17

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

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