Clinical Trials Register

Summary
EudraCT Number:	2012-005702-22
Sponsor's Protocol Code Number:	IELSG39
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:	2013-02-06
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

2012-005702-22

A.3

Full title of the trial

International prospective Phase 2 trial addressing the efficacy of first-line
Chlamydophila psittaci-eradicating therapy with protracted administration of
doxycycline followed by eradication monitoring and antibiotic re-treatment at
infection re-occurrence in patients with newly diagnosed Ocular Adnexal Margina Zone Lymphoma (OAMZL).

Studio Internazionale Prospettico di fase 2 per valutare il ruolo di una terapia
prolungata di prima linea eradicante l’infezione da CHLAMYDOPHILA PSITTACI,
seguita da monitoraggio dell’eradicazione e ripetizione della terapia antibiotica
nei pazienti con re-infezione, in pazienti affetti da linfoma degli annessi orbitari
di nuova diagnosi.

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

IELSG39

A.4.1

Sponsor's protocol code number

IELSG39

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	INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP
B.1.3.4	Country	Switzerland
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	INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	FONDAZIONE ITALIANA LINFOMI ONLUS
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 ITALIANA LINFOMI ONLUS
B.5.2	Functional name of contact point	FIL SECRETARY
B.5.3	Address:
B.5.3.1	Street Address	Via Venezia, 16
B.5.3.2	Town/ city	Alessandria
B.5.3.3	Post code	15121
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390131206132
B.5.5	Fax number	00390131206132
B.5.6	E-mail	segreteria@filinf.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 (DOXYCYCLINE)
D.2.1.1.2	Name of the Marketing Authorisation holder	PHARMACIA Italia S.p.A.
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	DOXYCYCLINE
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.3.11 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

Patients with newly diagnosed Ocular Adnexal Marginal Zone Lymphoma (OAMZL)

Pazienti affetti da linfoma degli annessi orbitari di nuova diagnosi

E.1.1.1

Medical condition in easily understood language

Patients with newly diagnosed Ocular Adnexal Marginal Zone Lymphoma (OAMZL)

Pazienti affetti da linfoma degli annessi orbitari di nuova

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

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 establish in a prospective, multicentre phase 2 trial, the efficacy of an upfront targeted therapy consisting of Chlamydophila psittaci (Cp)-eradicating therapy with prolonged administration of doxycycline followed by eradication monitoring and antibiotic re-treatment at infection re-occurrence in patients with newly diagnosed OAMZL.

Stabilire in uno studio prospettico, multicentrico, di fase 2 l’efficacia di una terapia di prima linea eradicante l’infezione da Chlamydophila psittaci (Cp), con una somministrazione prolungata di doxiciclina seguita da monitoraggio dell’avvenuta eradicazione e ri-trattamento antibiotico in caso di reinfezione.

E.2.2

Secondary objectives of the trial

Not applicable.

Non applicabile.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histological diagnosis of OAMZL
2. Single or bilateral lesion (stage IE) localized to the ocular adnexae (conjunctiva, lachrymal gland or sac, orbit soft tissue)
3. Absence of B symptoms
4. Previously untreated patients
5. No systemic antibiotic therapy in the last 3 months
6. Age >18 years
7. ECOG PS 0-2
8. Negative HIV, HBV and HCV serology
9. Adequate bone marrow, renal, and hepatic function
10. No previous or concurrent malignancies with the exception of surgically cured carcinoma in situ of the cervix, carcinoma of the skin, prostatic cancer, or other cancers without evidence of disease at least from 5 years
11. Absence of any familial, sociological or geographical condition potentially hampering compliance with study & follow-up schedule
12. Sexually active patients of childbearing potential must implement adequate contraceptive measures during study participation
13. No concurrent treatment with other experimental drugs
14. Patient-signed informed consent obtained before registration

1. Diagnosi istologica di OAMZL
2. Lesione singola o bilaterale (stadio IE) localizzata agli annessi oculari
(congiuntiva, ghiandola lacrimale o sacco lacrimale, tessuti molli dell’orbita)
3. Assenza di sintomi B
4. Pazienti non pretrattati
5. Non assunzione di terapia antibiotica nei 3 mesi precedenti l’arruolamento
6. Età >18 anni
7. ECOG PS 0-2
8. Sierologia negativa per infezione da HIV, HBV e HCV.
9. Adeguata funzionalità midollare, renale, epatica
10. Assenza di neoplasie pregresse o concomitanti con l’eccezione di carcinoma in situ della cervice, carcinoma della cute, cancro della prostata
chirurgicamente asportati, o altre neoplasie in assenza di malattia nei 5 anni precedenti
11. Assenza di qualsiasi condizione familiare, sociologica, geografica che possa condizionare la compliance con lo studio e il follow-up
12. I pazienti in età fertile devono utilizzare adeguate misure contraccettive
13. Non trattamenti concomitanti con farmaci sperimentali
14. Firma del consenso informato

E.4

Principal exclusion criteria

1. Pregnant or lactating women
2. Known allergy to tetracycline
3. Patients unwilling to comply with the requirements of follow-up
4. Myasthenia gravis (tetracycline can exacerbate muscle weakness)
5. Systemic lupus erythematous (tetracycline can exacerbate this condition)
6. Patients with large or rapidly enlarging tumours requiring immediate
radiotherapy

1. Donne in gravidanza o allattamento
2. Allergia nota a tetracicline
3. Pazienti non disponibili ad effettuare le visite di follow-up
4. Miastenia grave (le tetracicline possono esacerbare la debolezza muscolare)
5. Lupus eritematoso sistemico (le tetracycline possono esacerbare questa
condizione)
6. Pazienti con malattia rapidamente ingravescente che richieda radioterapia

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the 2-year progression-free survival (PFS) of patients with newly diagnosed stage-IE OAMZL treated with the experimental strategy.

L’endpoint primario è la sopravvivenza libera da progressione (PFS) a 2 anni nei pazienti con OAMZL stadio IEA di nuova diagnosi che ricevono il trattamento sperimentale.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 years

2 anni

E.5.2

Secondary end point(s)

The secondary endpoints are:
1. Feasibility
2. Tolerability of prolonged administration of doxycycline
3. Activity (overall response rate)
4. Overall survival
5. Cp eradication rate
6. Infection re-occurrence rate
7. Assessment of prevalence of IRTA1 marker in OAMZL
8. Assessment of genetic lesions and gene expression changes in OAMZL and their possible relationship with Cp infection and response to treatment
9. Identification of possible SNPs associated with Cp infection in OAMZL patients
10. Identification of possible bacterial polymorphisms responsible for antibiotic resistance, infection recurrence or persistence.

Gli endpoint secondari sono:
1. Fattibilità
2. Tollerabilità di somministrazione prolungata di doxiciclina
3. Attività (overall response rate)
4. Sopravvivenza globale
5. Tasso di eradicazione di Cp
6. Tasso di re-infezione
7. Valutazione della prevalenza del marker IRTA1 nei OAMZL
8. Valutazione di lesioni genetiche e modificazioni di espressione genica nei
OAMZL e loro possibile relazione con l’infezione da Cp e la risposta al
trattamento
9. Identificazione di possibili SNPs associate con l’infezione da Cp nei pazienti con OAMZL
10. Identificazione dei possibili polimorfismi batterici responsabili della
resistenza agli antibiotici e della ricorrenza o persistenza dell’infezione

E.5.2.1

Timepoint(s) of evaluation of this end point

Infection re-occurrence rate at 3 years.
Overall Survival at 5 years.

Tasso di re-infezione a 3 anni.
Sopravvivenza Globale a 5 anni.

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

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

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

Switzerland

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

Ultima visita ultimo paziente in studio.

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)

All patients will be followed up for 10 years.
Up to the 5th year of FU: MRI and ophthalmologist evaluation will be performed at 3, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months from upfront doxycycline. Chlamydial infection will be monitored at baseline and at 3, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months from upfront doxycycline. From the 5th year of FU and up to the 10th year of FU only PFS and OS data will be collected but in case of relapse, Chlamydial inf. should be investigated.

Tutti i pazienti saranno seguiti per 10 anni. Fino al 5° anno di FU: RMN delle orbite e una visita oftalmologica verranno eseguite a 3, 12, 18, 24, 30, 36, 42, 48, 54 e 60 mesi dal trattamento con doxiciclina. L’infezione da Chlamydia verrà monitorata al basale e a 3, 12, 18, 24, 30, 36, 42, 48, 54, 60 mesi dalla doxiciclina.
Dal 5° anno FU sarnnoraccolti dati di OS e PFS. In caso di ricaduta andrà ricercata l'eventuale associazione con infezione da Chlamydia.

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

2013-03-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-03-07

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

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