Clinical Trials Register

Summary
EudraCT Number:	2012-005222-30
Sponsor's Protocol Code Number:	LANHD01-2012
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:	2013-01-11
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

2012-005222-30

A.3

Full title of the trial

Feasibility study to assess safety of high dose of lanreotide in net patients poorly controlled by standard doses of SSA

Sicurezza del trattamento con lanreotide ad alte dosi in pazienti affetti da tumori neuroendocrini scarsamente responsivi al trattamento con analoghi della somatostatina a dosi standard

A.3.1

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

Feasibility study to assess safety of high dose of lanreotide in net patients poorly controlled by standard doses of SSA

Sicurezza del trattamento con lanreotide ad alte dosi in pazienti affetti da tumori neuroendocrini scarsamente responsivi al trattamento con analoghi della somatostatina a dosi standard

A.3.2

Name or abbreviated title of the trial where available

Lanreotide at high dosages in NET

Lanreotide ad alte dosi in NET

A.4.1

Sponsor's protocol code number

LANHD01-2012

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	UNIVERSITA' DI GENOVA
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	Ipsen S.p.A.
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	DiMI di Genova
B.5.2	Functional name of contact point	Reparto di Endocrinologia
B.5.3	Address:
B.5.3.1	Street Address	Viale Benedetto XV, 6
B.5.3.2	Town/ city	Genova
B.5.3.3	Post code	16132
B.5.3.4	Country	Italy
B.5.4	Telephone number	010 353 7946
B.5.5	Fax number	010 353 8977
B.5.6	E-mail	55869@unige.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	IPSTYL*SC SIR 90MG
D.2.1.1.2	Name of the Marketing Authorisation holder	IPSEN SpA
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	LAN HD
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	90
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	Yes
D.3.11.13.1	Other medicinal product type	analogo della somatostatina

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

Neuroendocrine tumours

Tumori neuroendocrini

E.1.1.1

Medical condition in easily understood language

Neuroendocrine tumours

Tumori neuroendocrini

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

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	10052399
E.1.2	Term	Neuroendocrine tumour
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 primary study objective is to evaluate the safety of lanreotide 90 mg in double dose (lanreotide 180 mg) every 28 days in patients affected by well differentiated neuroendocrine tumours (WD NETs) with disease progression during standard treatment with SSA (lanreotide 120mg ooctreotide 30mg every 28 days).

L’obiettivo primario dello studio è di valutare la sicurezza di lanreotide 90 mg in doppia dose (lanreotide 180 mg) ogni 28 giorni in pazienti con NETs ben differenziati (WD NETs) in progressione in corso di trattamento standard con SSA (lanreotide 120mg o octreotide 30mg ogni 28 giorni).

E.2.2

Secondary objectives of the trial

Secondary study Objectives are efficacy evaluations through tumor, clinical and laboratory parameters.

Gli obiettivi secondari dello studio sono di valutare l’efficacia del farmaco in studio sulla base di parametri tumorali, clinici e di laboratorio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Subjects of both gender, aged ≥18 years AND ≤ 75 years 2) patients with histological diagnosis of WD NETs, defined according to the recent WHO classification for gastroentero pancreatic (WHO 2010), bronchial and thymic NET(WHO 2004) or with hepatic metastases documented through a bioptic exam and Occult Primary tumor; patient with or without carcinoid syndrome could be enrolled; 3) Patients on treatment with standard dosages of octreotide LAR (30 mg/28 days) or lanreotide Autogel (120 mg/28 days) in the 6 months before enrollment; 4) Patients with tumor/biochemical/ symptomatic disease progression 5) Urine negative pregnancy test for women of childbearing age. Female subjects of childbearing potential must be using an appropriate method of contraception like double-barrier contraception , oral estroprogestinic contraceptive or an intrauterine device (IUD). Patient must be willing to continue using it throughout the entire study period, until two month after the study end; if the patient is a man, if the partner is a childbearing potential female, he should agree to using appropriate method of contraception;

1) Maschi o femmine di età compresa tra 18 e 75 anni (inclusi); 2) Pazienti con diagnosi istologica di WD NETs, definiti secondo la più recente classificazione WHO per i NET gastro-entero-pancreatici (WHO 2010), bronchiali e timici (WHO 2004) oppure pazienti con metastasi epatiche da WD NET, documentate all’esame bioptico e tumore primitivo occulto. Potranno essere inclusi pazienti che presentino o meno sindrome da carcinoide. 3) Pazienti in corso di trattamento con octreotide LAR a dosi standard (30 mg/28 giorni) o lanreotide Autogel (120 mg/28 giorni) nei 6 mesi precedenti l’arruolamento; 4) Pazienti con progressione di malattia radiologica e/o biochimica e/o clinica (sindrome da carcinoide) 5) Le donne in età fertile dovranno avere un test di gravidanza su siero negativo all’arruolamento e dovranno utilizzare un metodo anticoncezionale efficace quale un doppio metodo di barriera, un contraccettivo estro-progestinico per via orale o un dispositivo intrauterino (IUD). La paziente dovrà concordare di utilizzare il metodo contraccettivo per due mesi dopo la somministrazione dell’ultima iniezione del farmaco previsto dalla sperimentazione. Se il paziente è un uomo, dovrà concordare con il fatto che in caso di fertilità della compagna dovranno essere adottati metodi anticoncezionali efficaci.

E.4

Principal exclusion criteria

1. patients initially not responsive to SSA 2. patient naive to any treatment to SSA analogues 3. stable disease on treatment with SSA at standard dosages; 4. previous surgical treatment for NET in the 4 weeks before enrollment or planned during the study; 5. symptomatic colelitiasis 6. unstable angina, supported ventricular tachycardia, ventricular fibrillation, myocardial infarction in three months before enrollment; 7. hepatic disease here included cirrhosis, chronic or active hepatitis, permanent increase of AST, ALT, alkaline phosphatase 2xULN (upper limit normal) or increase of AST, ALT, alkaline phosphatase 4xULN (upper limit normal) in patients with hepatic metastases, total bilirubin 1.5xULN or creatinine 1.5xULN; 8. Specific previous antitumor treatment, here included, chemotherapy, chemoembolization, radiotherapy, PRRT or interferon in the 6 months before enrollment or planned during the study (based in investigator judgment) 9. Previous neoplastic disease (excepted basal cell carcinoma, cervical carcinoma in situ or uterine cancer, thyroid microcarcinoma or thyroid and prostate carcinoma surgically eradicated). Patients with carcinoma diagnosis can be enrolled in the study only if treated with a curative intent and free from disease from at least 5 years; 10. Decompensated diabetes mellitus (HbA1c> 8%); 11. Pregnant or breast-feeding women; Female subjects of childbearing potential not using an appropriate anticonceptive method 12. Hypersensitivity to lanreotide 13. Presence of adverse events (grade>1 according to NCI CTCAE (Versione 3.0) criteria) related to SSA treatment at inclusion

1) Pazienti inizialmente non responsivi ai SSA; 2) Pazienti naïve da trattamento con analoghi SSA; 3) Stabilità di malattia in corso di trattamento con SSA a dosi standard; 4) Pregressa terapia chirurgica relativa al NET nelle 4 settimane precedenti l’arruolamento o programmata nel corso dello studio; 5) Colelitiasi sintomatica; 6) Angina instabile, tachicardia ventricolare sostenuta, fibrillazione ventricolare, anamnesi positiva per infarto miocardico nei tre mesi precedenti l’arruolamento; 7) Malattie epatiche tra cui cirrosi, epatite attiva o cronica, o persistente rialzo di AST, ALT, fosfatasi alcalina (FA) 2xULN (upper limit normal) oppure AST, ALT, fosfatasi alcalina (FA) 4xULN (upper limit normal) in pazienti con metastasi epatiche, bilirubina totale 1.5xULN o creatinina 1.5xULN; 8) Pregresso trattamento anti-tumorale specifico, tra cui chemioterapia, chemo-embolizzazione, radioterapia, PRRT o interferone negli ultimi 6 mesi oppure pianificazione di alcuni dei suddetti trattamenti durante lo studio (sulla base del giudizio dello sperimentatore); 9) Pregressa malattia neoplastica (fatta eccezione per carcinoma basocellulare, carcinoma in situ della cervice o dell’utero, microcarcinoma tiroideo o carcinoma tiroideo e prostatico eradicati chirurgicamente). I pazienti con anamnesi di carcinoma possono essere inclusi se trattati con scopo curativo e liberi da malattia da più di 5 anni; 10) Diabete mellito scompensato (HbA1c> 8%); 11) Donne in gravidanza o allattamento e donne in età fertile che non adottino un metodo anticoncezionale efficace; 12) Ipersensibilità a lanreotide; 13) Presenza di eventi avversi di severità di grado superiore a 1 secondo i criteri NCI CTCAE (Versione 3.0), considerati correlati al trattamento con SSA al momento dell’arruolamento.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint for safety evaluation, is the patient proportion that has at least a serious adverse event during treatment with lanreotide.

L’endpoint primario per la valutazione della safety è la “proporzione di pazienti con almeno un evento avverso serio (SAE) riportato nel corso del trattamento con lanreotide”.

E.5.1.1

Timepoint(s) of evaluation of this end point

At each visit

Ad ogni visita

E.5.2

Secondary end point(s)

Secondary safety end points: 1. Proportion of patient with at least an adverse event; 2. Proportion of patient with at least an adverse event related to study drug; 3. Proportion of patient with at least an adverse event grade 3 and 4 according to NCI CTCAE versione 3 classification; 4. Proportion of patient with at least an adverse event grade 3 and 4 according to NCI CTCAE versione 3 classification related to study drug; Efficacy secondary End point: 5. Time to progression (TTP) from first study drug assumption until disease progression or death due to the study disease; 6. Changes in lesions diameter after 6 and 12 months of study treatment from basal; 7. Proportion of patient with an improvement in disease symptoms (diarrea e/o flushing) after 6 and 12 months of study treatment from basal (in patients with symptomatic NET); 8. Changes in percentage in the mean diarrea and/or flushing episodes numbers after 6 and 12 months of study treatment from basal (in patients with symptomatic NET); 9. Percentage of patients with a globally satisfying symptoms improvement based on Likert scale after 6 and 12 months of study treatment (in patients with symptomatic NET); 10. Changes in 5-HIAA levels after 6 and 12 months of study treatment from basal (in patients with basal levels increased); 11. Changes in chromogranina A levels after 6 and 12 months of study treatment from basal (in patients with basal levels increased).

End point secondari di safety: 1. Proporzione di pazienti con almeno un evento avverso; 2. Proporzione di pazienti con almeno un evento avverso correlato con il trattamento sperimentale; 3. Proporzione di pazienti con almeno un evento avverso di grado 3 e 4 secondo la classificazione NCI CTCAE versione 3; 4. Proporzione di pazienti con almeno un evento avverso di grado 3 e 4 secondo la classificazione NCI CTCAE versione 3 correlato con il trattamento. End point secondari di efficacia: 5. Tempo di progressione di malattia (TTP) calcolato dal momento della prima somministrazione del trattamento previsto dallo studio fino alla data di progressione di malattia o del decesso legato alla patologia neoplastica.; 6. Variazione del volume delle lesioni bersaglio dopo 6 e 12 mesi di trattamento rispetto al basale; 7. Percentuale di pazienti con miglioramento dei sintomi (diarrea e/o flushing) dopo 6 e 12 mesi di trattamento rispetto al basale (nei pazienti con NET sintomatici); 8. Variazione in percentuale della media del numero di episodi di diarrea e/o flushing dopo 6 e 12 mesi di trattamento rispetto al basale (nei pazienti con NET sintomatici); 9. Percentuale di pazienti con miglioramento dei sintomi globalmente soddisfacente sulla base della scala di Likert dopo 6 e 12 mesi di trattamento (nei pazienti con NET sintomatici); 10. Variazione dei livelli di 5-HIAA dopo 6 e 12 mesi di trattamento rispetto al basale (nei pazienti con livelli basali aumentati); 11. Variazione dei livelli di cromogranina A dopo 6 e 12 mesi di trattamento rispetto al basale (nei pazienti con livelli basali aumentati).

E.5.2.1

Timepoint(s) of evaluation of this end point

See Paragraph ''Secondary end point'' for details

Vedere paragrafo ''End point secondario'' per dettagli

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

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Blood samples collection for pharmacokinetics isn’t a substudy but a procedure of the main protocol

La raccolta di campioni per la farmacocinetica non è sotto-studio ma procedura del protocollo princi

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

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

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

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)

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.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)

At the end of the study, the investigator will decide the most appropriate therapy for the patient.

Al termine dello studio il medico sperimentatore deciderà la terapia più appropriata per il proseguo del paziente.

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

2013-02-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-05

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