Clinical Trials Register

Summary
EudraCT Number:	2012-003632-23
Sponsor's Protocol Code Number:	NI-0501-04
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:	2012-10-22
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

2012-003632-23

A.3

Full title of the trial

A Phase 2/3 , Open-label, Single Arm, Multicentre Study to Assess Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Multiple Administrations of NI-0501, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, in Paediatric Patients with Primary Haemophagocytic Lymphohistiocytosis (HLH)

Studio di fase 2/3, in aperto, a singolo braccio, multicentrico, per valutare la sicurezza, tollerabilita' , farmacocinetica ed efficacia di somministrazioni intravenose multiple di NI-0501, un anticorpo monoclonale anti-interferone gamma (anti-IFNy), in pazienti pediatrici con Linfoistiocitosi Emofagocitica primaria (HLH)

A.3.1

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

A study to investigate the safety and efficacy of a new drug, NI-0501, in children with a disease that is called "Primary Haemophagocytic Lymphohistiocytosis".

Studio per valutare la sicurezza e l'efficacia di un nuovo farmaco, NI-0501, in bambini in cui una malattia chiamata ''Linfoistiocitosi Emofagocitica primaria''

A.4.1

Sponsor's protocol code number

NI-0501-04

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01818492

A.5.4

Other Identifiers

Name:

US IND

Number:

111015

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	NovImmune SA
B.1.3.4	Country	Switzerland
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	NovImmune SA
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Seventh Framework Programme for Research
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NovImmune SA
B.5.2	Functional name of contact point	Isabelle Fournet
B.5.3	Address:
B.5.3.1	Street Address	14 Chemin des Aulx
B.5.3.2	Town/ city	Plan-les-Ouates
B.5.3.3	Post code	1228
B.5.3.4	Country	Switzerland
B.5.5	Fax number	+41225938280
B.5.6	E-mail	NI-0501.clinops@novimmune.com

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/3/10/749
D.3 Description of the IMP
D.3.1	Product name	NI-0501
D.3.2	Product code	NI-0501
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	N/A
D.3.9.2	Current sponsor code	NI-0501
D.3.9.3	Other descriptive name	Human anti-interferon gamma monoclonal antibody
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	5
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	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

haemophagocytic lymphohistiocytosis

Linfoistiocitosi Emofagocitica

E.1.1.1

Medical condition in easily understood language

A rare, life-threatening condition affecting predominantly children. The disease is characterized by uncontrolled hyper-inflammation on the basis of underlying immune deficiencies.

Malattia rara ad esito infausto che colpisce la popolazione in età pediatrica.La malattia è caratterizzata da una iperinfiammazione non controllata causata da un deficit immunitario di base

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	SOC
E.1.2	Classification code	10010331
E.1.2	Term	Congenital, familial and genetic disorders
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 determine the safety and tolerability profile of multiple intravenous
(IV) administrations of NI-0501.
•To determine the efficacy and benefit/risk profile of NI-0501 in HLH
patients.
•To describe the PK profile of NI-0501 in HLH patients.
•To determine the PD effects (levels of circulating Total IFNγ and
biomarkers of its neutralization, namely CXCL9 and CXCL10)
•To define an appropriate NI-0501 therapeutic dose regimen for HLH.
•To determine other biomarkers, e.g. sCD25, IL-10
•To assess the immunogenicity of NI-0501.

• Determinare la sicurezza e il profilo di tollerabilità di più somministrazioni endovenose (iv) del farmaco NI-0501 .
• Determinare l'efficacia del farmaco NI-0501 e il profilo rischio/beneficio nei pazienti affetti da HLH .
• Descrivere il profilo farmacocinetico del farmaco NI-0501 nei pazienti affetti da HLH .
• Valutazione degli effetti farmacodinamici (livelli di IFNγ totale circolante e marcatori della sua neutralizzazione, cioè CXCL9 and CXCL10)
• Definire un regime di dosaggio terapeutico adeguato per il farmaco NI-0501 nei pazienti affetti da HLH
• De terminazione di altri biomarcatori, come per esempio CD-25 solubile, IL-10
• Valutare l'immunogenicità del farmaco NI-0501

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Primary HLH patients of both genders, up to and including 18 years at
diagnosis of HLH, or at an age appropriate to be treated in the
investigator's practice. The diagnosis must be made on the following
criteria (as per HLH-2004 protocol):
a. A molecular diagnosis or familial history consistent with primary HLH
OR
b. 5 out of 8 criteria below are fulfilled:
- Fever
- Splenomegaly
- Cytopenias affecting 2 of 3 lineages in the peripheral blood
(hemoglobin <90g/L; platelets <100x10^9/L; neutrophils <1x10^9/L)
- Hypertriglyceridemia (fasting triglycerides >3mmol/L or >265mg/dL)
and/or hypofibrinogenemia (≤1.5g/L)
- Hemophagocytosis in bone marrow, spleen or lymph nodes, with no evidence of malignancy
- Low or absent natural killer (NK)-cell activity
- Ferritin ≥500μg/L
- Soluble CD25 (sCD25; i.e. soluble IL-2 receptor) ≥2400U/mL
2. Presence of active disease as assessed by treating physician
3. Patients having already received HLH conventional therapy must fulfill one of the following criteria as assessed by the treating physician
- Having not responded
- Having not achieved a satisfactory response
- Having not maintained a satisfactory response
- Showing intolerance of conventional HLH treatment
At the time of enrollment, eligible patients might still be receiving
treatment (induction or maintenance) or might have discontinued it.
4. Informed consent signed by the patient (if ≥18 years old) or by their
legally authorized representative(s) with the assent of patients who are
legally capable of providing it.
5. Having received guidance on contraception for both male and female
patients sexually active and having reached puberty:
Females of child-bearing potential, having a negative pregnancy test at
screening and unless true abstinence is in line with the preferred and
usual lifestyle of the patient, must agree to use adequate method(s) of
birth control from screening until 6 months after receiving last dose of
the study drug. Males with partner(s) of child-bearing potential must
agree to take appropriate precautions to avoid fathering a child from
screening until 6 months after receiving last dose of the study drug.

1.Pazienti affetti da HLH di entrambi i sessi fino al 18° anno di età a cui è stata diagnosticata l'HLH, le diagnosi di HLH devono essere fatte sulla base dei seguenti criteri (come per il ptotocollo HLH-2004)
a. Una dignaosi molecolare o storia familiare consoistente con HLH primaria
O
b. Cinque degli otto criteri sottostanti sono
- Febbre
- Splenomegalia
- Citopenia che che interessa 2 di 3 linee nel sangueperiferico (emoglobina < 90g/L; piastrine < 100 x 109/L; neutrofili < 1 x 109/L
- Ipertriglicediremia (trigliceridi a digiuno ≥ 3 mmol/L o ≥ 265 mg/dL ) e/o ipofibrinogenemia (≤ 1.5 g/L )
- Emofagocitosi nel midollo osseo o milza o linfonodi senza evidenza di tumori
- Assenza o bassa attività delle cellule natural killer (NK)
- Ferritina ≥ 500 μg/L
- CD25 solubile (sCD25; es.. recettore solubile dell’ IL-2) ≥ 2400 U/mL.

2.presenza di malattia attiva nei pazienti come da valutazione del medico che effettua il trattamento

3. Pazienti che hanno già ricevuto una terapia convenzionale per la HLH devono soddisfare uno dei seguenti criteri come valutato dal medico che effettua il trattamento
-non hanno risposto
-non hanno raggiunto una risposta soddisfacente
Non hanno mantenutpo una risposta soddisfacente
Mostrano intolleranza al trattamento convenzionale di HLH,

Al momento dell’arruolamento, i pazienti eleggibili possono ancora essere in trattamento (induzione o mantenimento) o possono averlo già interrotto. .

4.Consenso informato firmato dal paziente (se maggiorenne), dal(i) legale(i) rappresentante(i) del
paziente con l’assenso dei pazienti che sono legalmente in grado di fornirlo.

5. I pazienti, maschi e femmine, che abbiano raggiunto la pubertà e che sono sessualmente attivi, devono aver ricevuto guida sulla misure di contraccezione: femmine in età fertile, con test di gravidanza negativo allo screening devono accettare l’utilizzo di metodo/i contraccettivi adeguati dallo screening fino a 6 mesi dopo aver ricevuto l’ultima dose del farmaco in studio, a meno che l’astinenza non sia in linea con lo stile di vita della paziente. Maschi con partner in età fertile devono accettare l’utilizzo di precauzioni adeguate per evitare una paternità, dallo screening fino a 6 mesi dopo aver ricevuto l’ultima dose del farmaco in studio.

E.4

Principal exclusion criteria

1. Diagnosis of secondary HLH consequent to a proven rheumatic or
neoplastic disease.
2. Body weight < 3 kg.
3. Patients treated with:
- any T-cell depleting agents (such as anti-thymocyte globulin [ATG],
anti-CD52) during the previous 2 weeks prior to screening
- any other biologic drug within 5 times their defined half-life period,
except for rituximab in case of documented B-cell EBV infection (a list of
some of the most commonly used biologic half-lives will be included in
the Study Specific Risk Management Plan).
4. Active mycobacteria, Shigella, Histoplasma Capsulatum,
Campylobacter, Leishmania or Salmonella infections.
5. Evidence of history of tuberculosis or latent tuberculosis.
6. Positive serology for HIV antibodies, hepatitis B surface antigen or
hepatitis C antibodies.
7. Presence of malignancy.
8. Patient who have another concomitant disease or malformation
severely affecting the cardiovascular, pulmonary, liver or renal function.
9. History of hypersensitivity or allergy to any components of the study
regimen.
10. Receipt of a live or attenuated live (including BCG) vaccine within the
last 12 weeks before screening.
11. Pregnant or lactating female patients.

1. Diagnosi di HLH secondaria conseguente a una patologia reumatica o neoplastica
provata
2. Peso corporeo < 3 kg
3. Pazienti trattati con:
- qualsiasi farmaco che riduce il numero di cellule T (quale l'ATG, anti-CD52) durante le 2 settimane precedenti allo screening
– qualsiasi altro farmaco biologico entro un periodo di 5 volte la sua emivita (fatta eccezione per l’utilizzo di rituximab per il trattamento di una infezione da EBV documentata in linfociti B) (una lista di alcune delle piu’ comuni emivite biologiche sarà inclusa nel Risk Management Plan dello studio ).

4. Infezioni attive da micobatteri, Histoplasma Capsulatum, Shigella, Campylobacter Salmonella o Leishmania

5. Evidenza di storia passata di tubercolosi o di tubercolosi latente

6. Sierologia positiva per gli anticorpi HIV, antigene di superficie dell'epatite B o anticorpi dell'epatite C

7. Presenza di neoplasie

8. I pazienti che hanno un'altra malattia concomitante/ malformazione che colpisce gravemente
la funzione cardiovascolare, polmonare, epatica o renale

9. Anamnesi di ipersensibilità o allergia a qualsiasi componente del farmaco in studio

10. Vaccinazione con vaccino vivo o vivo attenuato (compreso il vaccino BCG) entro le ultime 12 settimane precedenti allo screening.

11. Pazienti donne in stato di gravidanza o durante allattamento

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint
-Overall Response Rate, i.e. achievement of either Complete or Partial Response or HLH Improvement, at End of Treatment (EoT).

- Endpoint primario di efficacia
Percentuale di Risposta Complessiva, cioè il raggiungimento di una Risposta Completa o di una Risposta Parziale o del Miglioramento di HLH alla fine del trattamento

E.5.1.1

Timepoint(s) of evaluation of this end point

See E.5.1.

E.5.2

Secondary end point(s)

•Secondary efficacy endpoints:
•Time to Response any time during the study
•Durability of Response, i.e. maintenance of response achieved any time during the study until EoT and beyond (including data collected in the
long-term follow-up study NI-0501-05).
•Number of patients able to reduce glucocorticoids by 50% or more of
baseline dose.
•Number of patients able to proceed to HSCT, when deemed indicated.
•Survival at Week 8 (or EoT) and at the end of the study Long-term
survival (in particular D+30 and D+100 post-HSCT survival) will be assessed in the context of long-term study NI-0501-05.
•Serum concentration of NI-0501 to determine NI-0501 pharmacokinetic (PK) profile.
•Determination of pharmacodynamic (PD) effects (levels of circulating
total IFNγ and markers of its neutralization, namely CXCL9 and CXCL10).
•Determination of other biomarkers, e.g. sCD25, IL-10. Safety parameters to be collected and assessed:
- Incidence, severity, causality and outcomes of Adverse Events (serious
and non-serious), with particular attention being paid to infections
- Number of patients withdrawn for safety reasons
Other parameters:
- Level (if any) of circulating antibodies against NI-0501 to determine immunogenicity (ADA).

- Tempo di raggiungimento della risposta valutata in qualsiasi momento durante lo studio.
- Durata della risposta, cioè il mantenimento della risposta raggiunta in qualsiasi momento durante lo studio fino alla fine del trattamento e oltre (comprendendo i dati raccolti durante lo studio di follow-up a lungo termine NI-0501-05).
- Numero di pazienti nei quali è possibile una riduzione di almeno il 50% della dose basale di glucocorticoidi.
- Numero di pazienti che procedono ad HSCT, qualora indicato.
- Sopravvivenza alla Settimana 8 (o al termine del periodo di trattamento) e alla fine dello studio [la sopravvivenza a lungo termine (in particolare la sopravvivenza al giorno +30 e al giorno +100 dopo HSCT) sarà valutata nel contesto dello studio a lungo termine NI-0501-05].
- Concentrazione ematica di NI-0501 per determinare la farmacocinetica
- del farmaco nei pazienti
- Valutazione degli effetti farmacodinamici (livelli dell'IFN totale circolante e marcatori della sua neutralizzazione, cioè CXCL9 and CXCL10).

- Determinazione di altri biomarcatori, come per esempio CD-25 solubile, IL-10. - Parametri di sicurezza da raccogliere e valutare: - Incidenza, la gravità e gli esiti degli Eventi Avversi (seri e non seri) possibilmente correlati al farmaco NI-0501, con una particolare attenzione alle infezioni
- Numero di pazienti ritirati per problemi di sicurezza

- Altri parametri
- Livello (se presente) degli anticorpi circolanti contro il farmaco NI-0501 per determinare l'immunogenicità (ADA)

E.5.2.1

Timepoint(s) of evaluation of this end point

See E.5.2.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

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.8.2.4

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

Austria

Germany

Italy

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

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

Yes

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Newborns, infants and toddlers

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)

After study end, a separate long term follow-up study will allow long term safety surveillance, investigation of the impact of NI-0501 treatment on survival and post-HSCT outcome measures for all patients who will have received at least one dose of NI-0501 in the pilot study, and completion of the evaluation of NI-0501 PK profile.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Associazione Italiana di Ematologia e Oncologia Pediatrica
G.4.3.4	Network Country	Italy

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-12-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-08

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
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