Clinical Trials Register

Summary
EudraCT Number:	2016-001988-36
Sponsor's Protocol Code Number:	CCD-LMZYMAA1-08
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:	2020-11-05
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

2016-001988-36

A.3

Full title of the trial

A 24-month Multicenter, Open-label Phase II Trial Investigating the Safety and Efficacy of Repeated velmanase alfa (recombinant human alpha-mannosidase) Treatment in Pediatric Patients below 6 years of age with Alpha-Mannosidosis

Studio clinico di fase II, multicentrico, in aperto, della durata di 24 mesi, per valutare la sicurezza e l¿efficacia di somministrazioni ripetute di velmanase alfa (alfa mannosidasi umana ricombinante) in pazienti pediatrici, sotto i 6 anni di et¿, affetti da Alfa Mannosidosi

A.3.1

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

A study, conducted in several sites, with a duration of 2 years to evaluate the Safety and Efficacy of a new drug named velmanase alfa used in children with Alpha-Mannosidosis below 6 years of age

Studio condotto in diversi centri, della durata di due anni, per valutare la sicurezza e l'efficacia di un nuovo farmaco chiamato velmanase alfa utilizzato su bambini affetti da alfa-mannosidosi di et¿ inferiore ai 6 anni

A.3.2

Name or abbreviated title of the trial where available

A study, conducted in several sites, with a duration of 2 years to evaluate the Safety and Efficacy

Studio condotto in diversi centri, della durata di due anni, per valutare la sicurezza e l'efficacia

A.4.1

Sponsor's protocol code number

CCD-LMZYMAA1-08

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/122/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CHIESI FARMACEUTICI S.P.A.
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	Chiesi Farmaceutici 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	Chiesi Farmaceutici S.p.A.
B.5.2	Functional name of contact point	Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Via Palermo
B.5.3.2	Town/ city	Parma
B.5.3.3	Post code	43122
B.5.3.4	Country	Italy
B.5.6	E-mail	clinicaltrials_info@chiesi.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/3/04/260
D.3 Description of the IMP
D.3.1	Product name	Velmanase alfa
D.3.2	Product code	[rhLAMAN]
D.3.4	Pharmaceutical form	Powder for solution for injection
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	VELMANASE ALFA
D.3.9.1	CAS number	1492823-75-2
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	recombinant human alpha-mannosidase
D.3.9.4	EV Substance Code	SUB180967
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	10
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	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	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.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

Alfa-mannosidosis

Alfa-mannosidosi

E.1.1.1

Medical condition in easily understood language

Alfa-mannosidosis

Alfa-mannosidosi

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10032658
E.1.2	Term	Other specified disorders of carbohydrate transport and metabolism
E.1.2	System Organ Class	100000004850

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

The main objectives of this trial are to evaluate safety and efficacy of repeated velmanase alfa i.v. infusions in pediatric alpha-mannosidosis patients aged less than 6 years" as per section 2 of the study protocol

"Gli obiettivi principali dello studio consistono nel valutare la sicurezza e l'efficacia di infusioni (i.v) ripetute di velmanase alfa in pazienti pediatrici di et¿ inferiore ai 6 anni affetti da alfa-mannosidosi", come specificato nella sezione 2 del protocollo

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) Patient’s custodial parent(s) must provide signed ICF prior to the involvement of the patient in any trial-related activities;
2) The subject’s custodial parent(s) must have the ability to comply with the protocol;
3) The subject must have a confirmed diagnosis of alpha-mannosidosis as defined by alpha-mannosidase activity in leukocytes or fibroblasts < 10% of normal activity (historical data);
4) The subject must have an age at the time of screening < 6 years.

1) Il/i genitore/i del paziente devono fornire un consenso informato firmato prima del coinvolgimento del paziente nelle attività previste dallo studio;
2) Il/i genitore/i del paziente devono avere la capacità di comprendere a pieno il protocollo;
3) Al soggetto è stata diagnostica l’alfa-mannosidosi, cioè l’attività dell’enzima alfa-mannosidasi nei leucociti o nei fibroblasti è < 10% rispetto all’attività normale (dati storici);
4) Al momento dello screening il soggetto deve avere un’età < 6 anni.

E.4

Principal exclusion criteria

1) The subject’s diagnosis cannot be confirmed by alpha-mannosidase activity < 10% of normal activity;
2) Presence of known chromosomal abnormality and syndromes affecting psychomotor development, other than alpha-mannosidosis;
3) History of Bone Marrow Transplantation (BMT);
4) Presence of known clinically significant cardiovascular, hepatic, pulmonary, or renal disease or other medical conditions that, in the opinion of the Investigator, would preclude participation in the trial;
5) Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial;
6) Planned major surgery that, in the opinion of the Investigator, would preclude participation in the trial;
7) Participation in other interventional trials testing the IMP within the last 3 months.

1) La diagnosi del soggetto non può essere confermata dall’attività dell’enzima alfa-mannosidasi < 10% rispetto all’attività normale;
2) Presenza di anomalie e sindromi cromosomiche note che hanno un effetto sullo sviluppo psicomotorio diverso dall’alfa-mannosidasi;
3) Precedente trapianto di midollo osseo (BMT);
4) Presenza di disturbi cardiovascolari, epatici, polmonari o renali di rilevanza clinica, oppure altre condizioni che a giudizio del investigatore precludono la partecipazione allo studio;
5) Altre condizioni cliniche, malattie gravi o circostanze attenuanti che, a giudizio del medico, potrebbero precludere la partecipazione allo studio;
6) Importanti interventi chirurgici programmati che, a giudizio del medico, potrebbero precludere la partecipazione allo studio;
7) Partecipazione ad altri studi interventistici con IMP negli ultimi 3 mesi.

E.5 End points

E.5.1

Primary end point(s)

- Safety and tolerability of velmanase alfa as per:
o Adverse events (AEs, including infusion-related reactions [IRRs])
o Vital signs
o Clinical laboratory parameters (hematology, biochemistry and urinalysis)
- Detection of anti-velmanase alfa-immunoglobulin G (IgG) antibodies

- Sicurezza e tollerabilità di velmanase alfa in relazione a:
o Eventi avversi (AE, incluse reazioni alle infusioni [IRR])
o Segni vitali
o Parametri clinici di laboratorio (ematologia, biochimica e analisi delle urine)
- Identificazione di anticorpi alfa-immunoglobuline G [IgG] anti-velmanase

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

E.5.2

Secondary end point(s)

- Efficacy outcomes:
o Serum oligosaccharides
o Functional capacity
o Endurance
o Hearing
o Immunological profile
o CSF biomarkers
o Assessment of quality of life via Questionnaire
o Assessment of mannose-rich oligosaccharides in brain tissue
o Magnetic Resonance Imaging (MRI)
- Pharmacokinetic parameters

- Risultati di efficacia:
o Oligosaccaridi nel siero
o Capacit¿ funzionale
o Resistenza
o Udito
o Profilo immunologico
o Biomarcatori del liquido cerebrospinale (CSF)
o Valutazione della qualit¿ della vita tramite questionario
o Valutazione degli oligosaccaridi ricchi di mannosio nel tessuto cerebrale
o Imaging a Risonanza Magnetica (MRI)
- Parametri farmacocinetici

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

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

Detection of anti-velmanase alfa-immunoglobulin G (IgG) antibodies

Identificazione di anticorpi alfa-immunoglobuline G [IgG] anti-velmanase

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

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

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

LPLV

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.1.1.1

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

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

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

The subjects are children (< 6 years old) and they are not allowed to
decide participation themselves. Both parents should consent if the
child, verbally and bodily, agrees to participate in this trial.

I soggetti sono bambini (di et¿ inferiore ai 6 anni) e non possono prendere decisioni in merito alla loro partecipazione in modo autonomo. Entrambi I genitori dovrebbero dare il consenso se il proprio figlio acconsentisse (verbalmente o fisicamente)

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)

Participants will be treated after the trial end as decided by PI. The treatment will not differ from expected normal treatment of alfa-mannosidosis, in children <6 years.

Alla fine dello studio I soggetti riceveranno il trattamento disponibile pi¿ appropriato secondo l'opinione del PI. Il trattamento non sar¿ diverso da quanto previsto normalmente per l'alfa-mannosidosi nei bambini di et¿ inferiore ai 6 anni

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

2018-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-17

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

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