Clinical Trials Register

Summary
EudraCT Number:	2009-016879-29
Sponsor's Protocol Code Number:	IPR/22.E
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-12-13
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2009-016879-29

A.3

Full title of the trial

NGR015: Randomised double-blind phase III study of NGR-hTNF plus best investigator's choice (BIC) versus placebo plus BIC in previously treated patients with advanced malignant pleural mesothelioma (MPM)

NGR015: essai de phase III comparatif en double-aveugle, randomisé, portant sur l’administration de NGR-hTNF + BIC (meilleure option thérapeutique) comparée à l’administration d’un placebo + BIC chez des patients préalablement traités atteints d’un mésothéliome pleural malin (MPM) avancé

NGR015: Gerandomiseerd, dubbelblind fase III-onderzoek van NGR-hTNF plus ‘best investigator’s choice’ (BIC) tegenover placebo plus BIC bij eerder behandelde patiënten met gevorderd maligne pleuraal mesothelioom (MPM)

A.3.1

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

Study of efficacy and safety of the compound NGR-hTNF in patient with advanced malignant pleural mesothelioma

Étude de l'efficacité et la sécurité du composé NGR-hTNF chez un patient à un stade avancé de mésothéliome pleural malin

Studie van de werkzaamheid en de veiligheid van de verbinding NGR-hTNF bij patiënten met gevorderde maligne mesothelioom van de pleura

A.3.2

Name or abbreviated title of the trial where available

NGR015

A.4.1

Sponsor's protocol code number

IPR/22.E

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	MOLMED
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	MOLMED SPA
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	Innopharma Srl
B.5.2	Functional name of contact point	Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	via Lavoratori Autobianchi 1
B.5.3.2	Town/ city	Desio (MB)
B.5.3.3	Post code	20832
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39362573128
B.5.5	Fax number	+39362544211
B.5.6	E-mail	d.scanniffio@innopharma.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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/08/549
D.3 Description of the IMP
D.3.1	Product name	NGR-hTNF
D.3.2	Product code	MM102
D.3.4	Pharmaceutical form	Concentrate 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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	MM102
D.3.9.3	Other descriptive name	NA
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	DOXORUBICIN
D.3.2	Product code	DOXORUBICIN
D.3.4	Pharmaceutical form	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	Doxorubicin
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	anthracycline
D.IMP: 3
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.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	gemcitabine
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	gemcitabine
D.3.9.1	CAS number	NA
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	range
D.3.10.3	Concentration number	200 to 1000
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	pyrimidine analog
D.IMP: 4
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.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	vinorelbine
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Vinorelbine
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 50
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	vinca alKaloid

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced malignant pleural mesothelioma previuosly treated with a pemetrexed based chemotherapy regimen

MPM avancé précédemment traité avec une chimiothérapie à base de pemetrexed

Gevorderd MPM, eerder behandeld met chemotherapie op basis van pemetrexed

E.1.1.1

Medical condition in easily understood language

Patient suffering of pleural cancer (pleural mesothelioma) that have already received chemotherapy (not more than 1 treatment with the "pemetrexed" chemotherapy)

Patient avec cancer de la plèvre (mésothéliome pleural) qui ont déjà reçu une chimiothérapie (pas plus de 1 traitement avec le pemetrexed)

Patiënt met borstvlieskanker (pleura mesothelioom), die reeds zijn behandeld met chemotherapie (niet meer dan 1 behandeling met de "pemetrexed" chemotherapie)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	PT
E.1.2	Classification code	10035605
E.1.2	Term	Pleural mesothelioma malignant advanced
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare overall survival (OS) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC

Comparer la survie globale (OS) chez des patients randomisés traités au NGR-hTNF + BIC par rapport à des patients randomisés traités au placebo + BIC

Vergelijken van algemene overleving (OS) bij patiënten die naar NGR-hTNF plus BIC zijn gerandomiseerd tegenover patiënten die naar placebo plus BIC zijn gerandomiseerd

E.2.2

Secondary objectives of the trial

-To compare progression-free survival (PFS)
-To compare disease control rate (DCR, defined as the percentage of patients who have a best response rating of complete or partial response or stable disease, according to MPM-modified RECIST criteria)
-To compare duration of disease control
-To evaluate safety and toxicity profile related to NGR-hTNF
-To assess changes in quality of life (QoL) in the two treatment arms
-To evaluate medical care utilization in the two treatment arms

-Comparer la survie sans progression (PFS)
-Comparer le taux de contrôle de la maladie (DCR, défini comme le pourcentage de patients qui ont un meilleur taux de réponse complète, de réponse partielle ou de stabilisation de la maladie, selon les critères RECIST modifiés pour le MPM)
-Comparer la durée du contrôle de la maladie
-Evaluer le profil de sécurité et de toxicité du NGR-hTNF
-Evaluer les changements intervenus dans la qualité de vie (QoL) dans les deux groupes de traitement
-Evaluer l’utilisation des soins médicaux dans les deux groupes de traitement

-Vergelijken van progressievrije overleving (PFS)
-Vergelijken van percentage ziektecontrole (DCR, gedefinieerd als het percentage patiënten met de beste responsscore van volledige of gedeeltelijke respons of stabiele ziekte, volgens de voor MPM gemodificeerde RECIST-criteria)
-Vergelijken van duur van ziektecontrole
-Beoordelen van veiligheids- en toxiciteitsprofiel van NGR-hTNF
-Beoordelen van veranderingen in kwaliteit van leven (QoL) in de twee behandelingsarmen
-Beoordelen van gebruik van medische zorg in de twee behandelingsarmen

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

Substudy A: "Quality of Life Assessment" - 20 JAN 2010 version B
Objective: Assessment of the social wellbeing of the patient

Substudy B: "Medical Resource utilisation" - 20 JAN 2010 version B
Objective: Health Economic analyses

Sous-étude A: «Qualité de vie" - 20 JAN 2010 version B
Objectif: évaluation du bien-être social du patient

Sous-étude B: «L'utilisation des ressources médicales" - 20 JAN 2010 version B
Objectif: analyses économiques de la santé

Deelonderzoek A: "Kwaliteit van leven" - 20 JAN 2010 versie B
Doelstelling: Evaluatie van de sociale welzijn van de patiënt

Deelonderzoek B: "Gebruik van medische middelen" - 20 JAN 2010 versie B Doelstelling: Gezondheid Economische analyses

E.3

Principal inclusion criteria

1.Age ≥ 18 years
2. Histologically or cytological confirmed malignant pleural mesothelioma of any of the following subtype:
epithelial, sarcomatoid, mixed, or unknown
3. Prior treatment with no more than one sistemic pemetrexed-based chemotherapy regimen administered
for advanced or metastatic disease. Prior use of a biological agent in combination with a pemetrexed based
regimen and prior administration of intrapleural cytotoxic agents are allowed.Patients who have previously received anthracyclines should not receive doxorubicin.
4. ECOG Performance Status 0 - 2
5. Life expectancy of ≥12 weeks
6. Adequate baseline bone marrow, hepatic and renal function, defined as follows:
a. Neutrophils ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL
b. Bilirubin ≤ 1.5 x ULN
c. AST and/or ALT ≤ 2.5 x ULN in absence of liver metastasis or ≤ 5 x ULN in presence of liver metastasis
d. Serum creatinine < 1.5 x ULN
7. Measurable or non-measurable disease according to MPM-modified RECIST criteria
8. Patients may have had prior therapy providing the following conditions are met:
a. Surgery: wash-out period of 14 days
b.Systemic anti-tumor and radiation therapy: wash-out period of 28 days
9. Patients must give written informed consent to participate in the study

1.Age ≥ 18 ans
2.Mésothéliome pleural malin histologiquement ou cytologiquement confirmé ou l’un des sous-types suivants: épithélial, sarcomatoïde, mixte ou inconnu
3.Traitement antérieur avec max. une chimiothérapie systémique à base de pemetrexed administrée pour un cancer avancé ou métastatique. Sont admises l’utilisation antérieure d’un agent biologique associé à la chimiothérapie à base de pemetrexed et l’administration antérieure d’agents cytotoxiques par voie intrapleurale. Les patients qui ont reçu précédemment des anthracyclines ne pourront pas recevoir de doxorubicine.
4.Indice de Performance ECOG 0 - 2
5.Espérance de vie ≥ 12 semaines
6.Bilan satisfait à l’inclusion, pour la moelle osseuse et les fonctions hépatique et rénale, défini comme suit : a.Neutrophiles ≥ 1,5 x 109/l; plaquettes ≥ 100 x 109/l; hémoglobine ≥ 9 g/dl;
b.Bilirubine ≤ 1,5 x LNS; c.AST et/ou ALT ≤ 2,5 x LNS en l’absence de métastases hépatiques ou ≤ 5 x LNS en présence de métastases hépatiques; d. Créatinine sérique < 1,5 x LNS
7.Maladie mesurable ou non-mesurable selon les critères RECIST modifiés pour le MPM
8.Les patients peuvent avoir été précédemment traités pour autant que les conditions suivantes soient remplies :
a.Chirurgie: période de wash-out de 14 jours
b.Traitement anticancéreux systémique et radiothérapie: période de wash-out de 28 jours
9.Les patients doivent donner par écrit leur consentement informé pour participer à l’essai.

1.Leeftijd ≥ 18 jaar
2.Histologisch of cytologisch bevestigd maligne pleuraal mesothelioom van een van de volgende subtypen: epitheliaal, sarcomatoïde, gemengd of onbekend
3.Eerdere behandeling met niet meer dan één systemische chemotherapie op basis van pemetrexed, toegediend voor gevorderde of gemetastaseerde ziekte. Eerder gebruik van een biologisch middel in combinatie met chemotherapie op basis van pemetrexed en eerdere toediening van intrapleurale cytotoxische middelen zijn toegestaan. Patiënten die eerder anthracyclinen kregen toegediend, mogen geen doxorubicine krijgen.
4.ECOG Performance Status 0 - 2
5.Levensverwachting van ≥ 12 weken
6.Toereikende nulmeting van beenmerg, lever- en nierfunctie, als volgt gedefinieerd: a.Neutrofielen ≥ 1,5 x 109/l; bloedplaatjes ≥ 100 x 109/l; hemoglobine ≥ 9 g/dl; b.Bilirubine ≤ 1,5 x ULN; c. AST en/of ALT ≤ 2,5 x ULN in afwezigheid van levermetastase of ≤ 5 x ULN in aanwezigheid van levermetastase; d.Serum creatinine < 1,5 x ULN
7.Meetbare of niet-meetbare ziekte volgens de voor MPM gemodificeerde RECIST-criteria
8.Patiënten mogen eerdere therapie hebben ondergaan, mits aan de volgende voorwaarden wordt voldaan: a. Operatie: wash-out-periode van 14 dagen; b.Systemische antitumor- en bestralingstherapie: wash-out-periode van 28 dagen
9.Patiënten moeten schriftelijke toestemmingsverklaring hebben gegeven om aan het onderzoek deel te nemen

E.4

Principal exclusion criteria

1. Patients must not receive any other investigational agents while on study
2. Patients with myocardial infarction within the last six months, unstable angina, New York Heart association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication
3. Uncontrolled hypertension
4. QTc interval (congenital or acquired) > 450 ms
5. History or evidence upon physical examination of CNS disease unless adequately treated (e.g., primary brain tumor, any brain metastasis, seizure not controlled with standard medical therapy, or history of stroke)
6. Patients with active or uncontrolled systemic disease/infections or with serious illness or medical conditions, which is incompatible with the protocol
7. Known hypersensitivity/allergic reaction to human albumin preparations or to any of the excipients
8. Any psychological, familial, sociological or geographical condition potentially tampering compliance with the study protocol
9. Pregnancy or lactation.

1.Les patients ne peuvent recevoir aucun autre agent expérimental pendant l’essai
2.Patients avec un infarctus du myocarde dans les six derniers mois, angine instable, insuffisance cardiaque congestive de grade II et plus selon la classification NYHA (New York Heart Association), arythmie sévère sous traitement
3.Hypertension incontrôlée
4.Intervalle QTc (congénital ou acquis) > 450 ms
5.Antécédents ou présence attestée par un examen médical d’une pathologie du SNC sauf si elle est adéquatement traitée (par ex., tumeur cérébrale primitive, métastase cérébrale quelconque, épilepsie non contrôlée avec une thérapie médicale standard ou antécédent d’accident vasculaire cérébral)
6.Patients qui présentent une pathologie/infection systémique active ou incontrôlée ou une maladie grave ou des conditions médicales incompatibles avec le protocole
7.Hypersensibilité ou réaction allergique connue aux préparations à base d’albumine humaine ou à tout autre excipient
8.Suivi clinique impossible pour des raisons psychologiques, familiales, sociales ou géographiques
9.Femme enceinte ou allaitant.

1.Patiënten mogen gedurende het onderzoek geen andere onderzoeksmiddelen ontvangen
2.Patiënten met myocardinfarct in de laatste zes maanden, onstabiele angina, congestief hartfalen klasse II of hoger volgens de New York Heart Association (NYHA) of ernstige hartaritmie die medicatie vereist
3.Niet-gecontroleerde hypertensie
4.QTc-interval (aangeboren of verworven) > 450 ms
5.Voorgeschiedenis of aanwijzingen na lichamelijk onderzoek van CZS-ziekte, tenzij afdoende behandeld (bv. primaire hersentumor, hersenmetastase, niet met standaardmedicatie gecontroleerd insult of voorgeschiedenis van herseninfarct)
6.Patiënten met actieve of niet-gecontroleerde systemische ziekte/infecties of met ernstige ziekte of medische aandoeningen die niet met het protocol verenigbaar zijn
7.Bekende overgevoeligheid voor of allergische reactie op humaan albumine of op een van de hulpstoffen
8.Een psychologische, familiale, sociologische of geografische toestand die mogelijk de naleving van het onderzoeksprotocol belemmert
9.Zwangerschap of borstvoeding

E.5 End points

E.5.1

Primary end point(s)

To compare overall survival (OS) in patients randomised to NGR-hTNF plus BIC (Best Investigator Choice) versus patients randomised to placebo plus BIC.

Comparer la survie globale (OS) chez des patients randomisés traités au NGR-hTNF + BIC par rapport à des patients randomisés traités au placebo + BIC

Vergelijken van algemene overleving (OS) bij patiënten die naar NGR-hTNF plus BIC zijn gerandomiseerd tegenover patiënten die naar placebo plus BIC zijn gerandomiseerd

E.5.1.1

Timepoint(s) of evaluation of this end point

Time from the date of randomization until the date of death due to any cause or the last date the patient was known to be alive.

entre la date de randomisation et le décès, quelle qu’en soit la cause

de tijd vanaf de randomisatiedatum tot de datum van overlijden aan welke oorzaak dan ook.

E.5.2

Secondary end point(s)

- Progression-free survival (PFS)
- Disease control rate (DCR)
- Duration of disease control
- Safety
- Quality of life (QoL)
- Medical Care Utilization (MCU)

-Survie sans progression (PFS)
-Taux de contrôle de la maladie (DCR)
-Durée de contrôle de la maladie
-Sécurité et tolérabilité
-Qualité de vie
-Utilisation des ressources médicales

-Progressievrije overleving (PFS)
-Percentage ziektecontrole (DCR)
-Duur van ziektecontrole
-Veiligheid en verdraagbaarheid
-Kwaliteit van leven
-Gebruik van medische middelen

E.5.2.1

Timepoint(s) of evaluation of this end point

- Progression-free survival (PFS): time from the date of randomization until disease progression, or death due to any cause

Survie sans progression (PFS): le temps écoulé entre la date de randomisation et la progression de la maladie ou le décès, quelle qu’en soit la cause

Progressievrije overleving (PFS): de tijd vanaf de randomisatiedatum tot ziekteprogressie of overlijden aan welke oorzaak dan ook

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of Life assessment

Qualité de vie

Kwaliteit van leven

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Canada

Egypt

Ireland

Italy

Netherlands

Poland

Spain

Sweden

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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

The end of study corresponds to the date of close-out visit in the last centre. In fact, study data will be validated and study documents will be reviewed within close-out visit.

La fin de l'étude correspond à la date de close-out visite dans le dernier centre

Het einde van de studie komt overeen met de datum van de close-out bezoek in het laatste centrum

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:

390

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

390

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2011-12-13.

Yes

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

192

F.4.2.2

In the whole clinical trial

390

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)

After the study partecipation, patient will be treated according to the best choice of the investigator. No reccomandations in regards is mentioned in the protocol

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

2012-03-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-12-18

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