Clinical Trials Register

Summary
EudraCT Number:	2014-004499-47
Sponsor's Protocol Code Number:	ZENITH
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:	2015-05-21
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

2014-004499-47

A.3

Full title of the trial

A case control, phase II, monocentric, randomized study, utilizing Zinc as enhancer of immune recovery and immune reconstitution in auto-transplant for multiple myeloma

Studio clinico randomizzato in aperto per valutare l’efficacia della supplementazione con Zinco in pazienti sottoposti a trapianto di cellule staminali autologhe per malattie ematologiche

A.3.1

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

study, utilizing Zinc as enhancer of immune recovery and immune reconstitution in auto-transplant for multiple myeloma

Studio clinico per valutare l'efficacia della supplementazione con zinco in pazienti sottoposti a trapianto di cellule staminali per malattie ematologiche

A.3.2

Name or abbreviated title of the trial where available

ZENITH

A.4.1

Sponsor's protocol code number

ZENITH

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	AZIENDA OSPEDALIERO-UNIVERSITARIA PISANA
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	Azienda Farmaceutica: IDI FARMACEUTICA
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	U.O. EMATOLOGIA - AOUP
B.5.2	Functional name of contact point	SEZIONE "TMO" edificio 11
B.5.3	Address:
B.5.3.1	Street Address	via Roma 67
B.5.3.2	Town/ city	Pisa
B.5.3.3	Post code	56126
B.5.3.4	Country	Italy
B.5.4	Telephone number	050-993085
B.5.5	Fax number	050-992903
B.5.6	E-mail	s.giorgi@med.unipi.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	ZINCO SOLFATO IDI - 200 MG COMPRESSE 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	IDI FARMACEUTICI S.R.L.
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	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ZINCO SOLFATO
D.3.9.1	CAS number	7733-02-0
D.3.9.2	Current sponsor code	Zinco solfato
D.3.9.3	Other descriptive name	ZINCO SOLFATO
D.3.9.4	EV Substance Code	SUB15762MIG
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	200
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

Multiple Myeloma

Mieloma multiplo

E.1.1.1

Medical condition in easily understood language

Multiple Myeloma

Mieloma multiplo

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Laboratory study of the immune reconstitution after auto-graft in patients treated with Zinc supplementation

Vantaggio del rendimento timico nel gruppo trattato.

E.2.2

Secondary objectives of the trial

Demonstration of less infectious disease, early B and T cell count recovery, higher overall-response rate in the treated arm

minore incidenza di episodi infettivi nel gruppo trattato rispetto al gruppo non trattato.
- potenziale recupero precoce della linfopoiesi B e della produzione di immunoglobuline.
- maggiore percentuale di ORR e CR e minore incidenza di recidive nel gruppo trattato rispetto al gruppo non trattato, indipendentemente dalla composizione del graft.
- rilevazione degli eventuali effetti collaterali della terapia con zinco.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Multiple myeloma, component M, not previously subjected to auto or allo-transplant, eligible to autologous PBSC.
• Candidates for conditioning with MEL 200 (melphalan 200 mg/sqm in two doses in one day of treatment) for patients younger than 65 years, MEL 100 (melphalan 100/sqm, in two doses, one-day of therapy) for patients aged between 65 and 70 years.
• Treatment with one or two prior lines of therapy, with apheresis made with high-dose cyclophosphamide and g-CSF
• Aged between 18 and 70 years old, both sexes
• Good general health except for the manifestations of multiple myeloma, or for frequent neurological complications related to drugs used in multiple myeloma (paresthesia, peripheral sensory neuropathy)
• free diet foods fortified with zinc.
• Signature of the informed consent form.

• Mieloma multiplo, con componente monoclonale completa, non precedentemente sottoposti ad auto o allo-trapianto, elegibili ad autotrapianto di PBSC.
• Candidati a condizionamento con MEL 200 (melphalan 200 mg/mq, in due somministrazioni, in un unico giorno di terapia) per pazienti di età inferiore ai 65 anni, MEL 100 (melphalan 200 mg/mq, in due somministrazioni, in un unico giorno di terapia) per i pazienti di età compresa tra i 65 e i 70 anni.
• Trattamento pregresso con una o due linee di terapia, con staminoaferesi effettuata con ciclofosfamide ad alte dosi e fattore di crescita granulocitario
• Età compresa tra i 18 ed i 70 anni, entrambi i sessi
• Buone condizioni di salute generale eccetto che per le manifestazioni del mieloma multiplo o per le frequenti complicanze neurologiche legate ai farmaci utilizzati nel mieloma multiplo (parestesie, neuropatia sensitiva periferica)
• Dieta priva di alimenti arricchiti con zinco. Tale criterio verrà valutato all’anamnesi.
• Firma del modulo di consenso informato.

E.4

Principal exclusion criteria

• Any contraindications to zinc or hypersensitivity to any of the excipients
• Diet foods fortified with zinc
• Taking supplements containing zinc or other substances, anti-oxidants
• Inability to consent to participate in the study
• Pregnancy or breastfeeding

• Eventuali controindicazioni allo zinco o ipersensibilità ad uno degli eccipienti
• Dieta con alimenti arricchiti di zinco
• Assunzione di integratori contenenti zinco o di altre sostanze anti-ossidanti
• Incapacità di acconsentire a partecipare allo studio
• Gravidanza o allattamento

E.5 End points

E.5.1

Primary end point(s)

Advantage of thymic performance in zinc-treated group. Instruments to be used: Analysis of TRECs, flow cytometric analysis of lymphocyte subpopulations T ( Absolute values and percentages of lymphocyte populations , maturational stage of circulating lymphocytes, presence of naive lymphocytes in the peripheral blood) and Functional Test (stimulation with mitogens, superantigens and anti- CD3, dosage in the supernatant of IFN, IL- 5, IL-12 and TNF- alpha). Dosage of baseline zinchemia. The effect will be misurate also with the assay of serum thymulin (RIA)

Vantaggio del rendimento timico nel gruppo trattato. Strumenti da utilizzare: analisi dei TRECs, analisi citofluorimetrica delle sottopopolazioni linfocitarie T (valori percentuali e assoluti delle popolazioni linfocitarie, stadio maturativo dei linfociti circolanti, presenza di linfociti naive su sangue periferico) e test funzionali (stimolazione con mitogeni, superantigeni e anti-CD3, con dosaggio nel sovranatante di citochine quali IFNgamma, IL-5, IL-12 e TNF alfa), indipendentemente dallo stato basale di zinchemia del paziente. L’effetto sarà misurato indirettamente anche con il dosaggio della timulina sierica (metodica RIA).

E.5.1.1

Timepoint(s) of evaluation of this end point

At the first day of stem cell collection The day of beginning of the conditioning Day +30 after stem cell infusion Day +100 after stem cell infusion

0) Giorno della prima staminaferesi 1) Giorno prima dell’inizio del condizionamento pre-trapianto 2) Giorno +30 dal trapianto 3) Giorno +100 dal trapianto

E.5.2

Secondary end point(s)

1-lower incidence of infectious episodes in the treatment group compared to the untreated group. Tools to use: visits. A history of febrile episodes . Physical examination . Imaging tests, test cultivation and isolation by biological samples (blood cultures, cultures from sputum, detection of antigens, antibodies, specific PCR genomes of bacteria, fungi , viruses, parasites), if the patient reports suspicious incidents or presents fever.
2-potential early recovery of B lymphopoiesis and immunoglobulin production. Instruments to be used : flow cytometry on peripheral blood on B lymphocytes, determination of serum immunoglobulins
3-Greater percentage of ORR and CR and lower incidence of recurrence of disease in the treated group compared to the untreated group, regardless of the composition of the graft. Tools to use: serum protidogramma, immunofixation on urine and serum, dosage of free light – chain, assay of IgG , IgA , IgM, bone marrow biopsy, skeletal surveys (RX, MRI, PET). All of the above tests are normally inserted in the re-staging program after transplant
4-Detection of the possible side effects of treatment with zinc. Tools to use: history, physical examination, any specific diagnostic tests to be established on the basis of the symptoms reported.

1-minore incidenza di episodi infettivi nel gruppo trattato rispetto al gruppo non trattato. Strumenti da utilizzare: visite di controllo. Anamnesi di episodi febbrili. Esame obiettivo. Esami di imaging, test colturali e di isolamento su campioni biologici (emocolture, colture da escreato, ricerca di antigeni , ricerca di anticorpi specifici, PCR per genomi di batteri, funghi, virus, parassiti), qualora il paziente riferisca episodi sospetti o si presenti piretico
2-potenziale recupero precoce della linfopoiesi B e della produzione di immunoglobuline. Strumenti da utilizzare: citofluorimetria su sangue periferico per linfociti B. Dosaggio delle immunoglobuline sieriche
3-maggiore percentuale di ORR e CR e minore incidenza di recidive nel gruppo trattato rispetto al gruppo non trattato, indipendentemente dalla composizione del graft. Strumenti da utilizzare: protidogramma sierico, immunofissazione siero-urinaria, dosaggio delle free-light chain, dosaggio di IgG, IgA, IgM, biopsia osteomidollare, indagini scheletriche (RX, RMN, PET). Tutti i suddetti esami sono normalmente inseriti nell’iter di rivalutazione della malattia nel post trapianto
4-Rilevazione degli eventuali effetti collaterali della terapia con zinco. Strumenti da utilizzare: anamnesi, esame obiettivo, eventuali test diagnostici specifici da stabilire sulla base dei sintomi lamentati

E.5.2.1

Timepoint(s) of evaluation of this end point

1-At the first day of stem cell collection The day of beginning of the conditioning Day +30 after stem cell infusion Day +100 after stem cell infusion
2-At the first day of stem cell collection The day of beginning of the conditioning Day +30 after stem cell infusion Day +100 after stem cell infusion
3-At the first day of stem cell collection The day of beginning of the conditioning Day +30 after stem cell infusion Day +100 after stem cell infusion
4-At the first day of stem cell collection The day of beginning of the conditioning Day +30 after stem cell infusion Day +100 after stem cell infusion

1-0) Giorno della prima staminaferesi 1) Giorno prima dell’inizio del condizionamento pre-trapianto 2) Giorno +30 dal trapianto 3) Giorno +100 dal trapianto
2-0) Giorno della prima staminaferesi 1) Giorno prima dell’inizio del condizionamento pre-trapianto 2) Giorno +30 dal trapianto 3) Giorno +100 dal trapianto
3-0) Giorno della prima staminaferesi 1) Giorno prima dell’inizio del condizionamento pre-trapianto 2) Giorno +30 dal trapianto 3) Giorno +100 dal trapianto
4-

0) Giorno della prima staminaferesi 1) Giorno prima dell’inizio del condizionamento pre-trapianto 2) Giorno +30 dal trapianto 3) Giorno +100 dal trapianto

At the first day of stem cell collection The day of beginning of the conditioning Day +30 after stem cell infusion Day +100 after stem cell infusion

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Trattamento con terapia standard in assenza di somministrazione di zinco solfato

Standard terapy without zinc supplementation

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

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)

Routinary follow up

Follow up routinario dei pazienti trapiantati di midollo

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

2015-02-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-16

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

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