Clinical Trials Register

Summary
EudraCT Number:	2018-001469-18
Sponsor's Protocol Code Number:	CT2-04-17
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:	2021-05-20
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

2018-001469-18

A.3

Full title of the trial

Treatment of beta-thalassemia patients with rapamycin (sirolimus): from pre-clinical research to a clinical trial

Trattamento di pazienti con beta-talassemia con Rapamicina (sirolimus): dalla ricerca pre-clinica ad uno studio clinico

A.3.1

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

Treatment of beta-thalassemia patients with rapamycin (sirolimus): from pre-clinical research to a clinical trial

Trattamento di pazienti con beta-talassemia con Rapamicina (sirolimus): dalla ricerca pre-clinica ad uno studio clinico

A.3.2

Name or abbreviated title of the trial where available

THALA-RAP

A.4.1

Sponsor's protocol code number

CT2-04-17

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	Dipartimento di Scienze della Vita e Biotecnologie dell'Università degli Studi di Ferrara
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	AIFA - Italian Medicines Agency
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	Dipartimento Scienze della Vita e Biotecnologie dell'Università degli Studi di Ferrara
B.5.2	Functional name of contact point	Dipartimento Scienze della Vita e B
B.5.3	Address:
B.5.3.1	Street Address	Via Fossato di Mortara, 74
B.5.3.2	Town/ city	Ferrara
B.5.3.3	Post code	44121
B.5.3.4	Country	Italy
B.5.4	Telephone number	0532974443
B.5.5	Fax number	0532455549
B.5.6	E-mail	roberto.gambari@unife.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	RAPAMUNE - 0.5 MG - COMPRESSE RIVESTITE - USO ORALE BLISTER(PVC/PE/ACLAR/ALU) 100 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/3/15/1585
D.3 Description of the IMP
D.3.1	Product name	Sirolimus 0.5 mg
D.3.2	Product code	[Sirolimus 0.5 mg]
D.3.4	Pharmaceutical form	Coated 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	00259300
D.3.9.1	CAS number	53123-88-9
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Rapamycin; Antibiotic AY 22989; Rapammune
D.3.9.4	EV Substance Code	SUB10537MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
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	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	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

Beta-thalassemia transfusion dependent patients

Pazienti con beta-talassemia dipendenti da trasfusione

E.1.1.1

Medical condition in easily understood language

Beta-thalassemia transfusion dependent patients

Pazienti con beta-talassemia dipendenti da trasfusione

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10043391
E.1.2	Term	Thalassaemia beta
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10043391
E.1.2	Term	Thalassaemia beta
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 evaluate the suitability of sirolimus for the treatment of beta-thalassemia patients within the frame of a comprehensive project aimed to the reduction of their transfusions need (consequently ameliorating their quality of life). This goal can be obtained through a pharmacologically mediated increased level of HbF, with a prerequisite to be verified, namely the correlation between induction of HbF in vitro and in vivo in single patients.

Valutare l’utilizzo di sirolimus per il trattamento dei pazienti beta-talassemici nell'ambito di un progetto globale volto alla riduzione delle loro necessità di trasfusioni (migliorando di conseguenza la loro qualità di vita). Questo obiettivo può essere ottenuto attraverso un aumento del livello di HbF farmacologicamente mediato, in seguito alla verifica della correlazione tra l'induzione di HbF in vitro e in vivo nei singoli pazienti

E.2.2

Secondary objectives of the trial

- To assess safety of sirolimus and correlation between administered dose and blood levels in beta-thalassemia patients,
- To assess the influence of sirolimus on transfusion regimen,
- To assess the effect of sirolimus on hematopoietic and immune system of thalassemia patients.

- Valutare la sicurezza di sirolimus e la correlazione tra dose somministrata e livelli ematici nei pazienti beta-talassemici,
- Valutare l'influenza di sirolimus sul regime trasfusionale
- Valutare l'effetto di sirolimus sul sistema ematopoietico e immunitario dei pazienti talassemici.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Responsive to the in vitro (ErPCs) treatment with sirolimus according to laboratory specific definition (= 20% increase of HbF in comparison with samples not treated with sirolimus);
2. AST or ALT < 3x ULN (Upper Limit of Normal);
3. Documented Platelet count >150.000/ul;
4. Patient willing to follow all the study requirements and perform all the study visits and to cooperate with the investigator;
5. Selection criteria must still be fulfilled at the time of the inclusion visit

1. Rispondere al trattamento in vitro (ErPC) con Sirolimus secondo la definizione specifica di laboratorio
2. AST o ALT <3x ULN (limite superiore della norma)
3. Conta piastrinica documentata > 150.000/ul
4. Paziente disposto a seguire tutti i requisiti dello studio ed eseguire tutte le visite di studio e collaborare con l'investigatore
5. I criteri di selezione devono ancora essere soddisfatti al momento della visita di inclusione

E.4

Principal exclusion criteria

1. Uncontrolled hypertension defined as systolic pressure (PA) = 140 mm Hg or diastolic pressure = 90 mm Hg;
2. Class 3 or higher heart failure (New York Heart Association, NYHA);
3. QTc> 450 msec on selection ECG;
4. White blood cell [WBC] count <3000 cells per µL and/or Granulocytes <1500/mm3;
5. Total cholesterol > 240 mg/dl;
6. Triglycerides > 200 mg/dl;
7. Proteinuria with urinary protein >1g/24 hrs;
8. Any active infection requiring parenteral antibiotic therapy within 28 days prior to inclusion or oral antibiotics within 14 days prior to inclusion;
9. Enrolment into one other drug or device trial since selection;
10. Major surgery (including splenectomy) performed after the study selection visit;
11. Ongoing treatment with drugs and agents that could increase the concentration of sirolimus in the blood including: ciclosporin, bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, protease inhibitors (eg for HIV and hepatitis C which require pharmacological treatment with ritonavir, indinavir, boceprevir and telaprevir), metoclopramide, nicardipine, troleandomycin, verapamil;
12. Ongoing treatment with drugs and agents that could reduce the concentration of sirolimus including carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's wort (Hypericum perforatum);
13. Cytotoxic agents, systemic corticosteroids, immunosuppressants or anticoagulant therapy such as warfarin or heparin within 28 days before inclusion (prophylactic aspirin up to 100 mg / day is allowed);
14. Macrolidic antibiotics (clarithromycin).
15. Occurrence of an event which leads to the appearance of a non-selection criteria.

1. Ipertensione non controllata definita come pressione sistolica (PA) = 140 mm Hg o pressione diastolica = 90 mm Hg
2. Insufficienza cardiaca di classe 3 o superiore (New York Heart Association, NYHA).
3. QTc > 450 msec sull'ECG di selezione.
4. Numero di globuli bianchi [WBC] <3000 cellule per µL e/o Granulociti <1500/mm3
5. Colesterolo totale >240 mg/dl
6. Trigliceridi >200 mg/dl
7. Proteinuria con proteina urinaria >1g/24 h;
8. Qualsiasi infezione attiva che richieda una terapia antibiotica parenterale entro 28 giorni prima dell'inclusione o degli antibiotici orali entro 14 giorni prima dell'inclusione;
9. Partecipazione ad un'altra sperimentazione con farmaci o dispositivi dalla selezione;
10. Interventi chirurgici maggiori (inclusa Ssplenectomia) eseguiti dopo la visita di selezione dello studio;
11. Trattamento in corso con farmaci e agenti che potrebbero aumentare la concentrazione di Sirolimus nel sangue tra cui: ciclosporina, bromocriptina, cimetidina, cisapride, clotrimazolo, danazolo, diltiazem, fluconazolo, inibitori della proteasi (ad es. Per HIV ed epatite C che richiedono un trattamento farmacologico ritonavir, indinavir, boceprevir e telaprevir), metoclopramide, nicardipina, troleandomicina, verapamil.
12. Trattamento in corso con farmaci e agenti che potrebbero ridurre le concentrazioni di Sirolimus inclusi carbamazepina, fenobarbital, fenitoina, rifapentina, erba di San Giovanni (Hypericum perforatum).
13. Agenti citotossici, corticosteroidi sistemici, immunosoppressori o terapia anticoagulante come warfarin o eparina entro 28 giorni prima dell'inclusione (è consentita l'aspirina profilattica fino a 100 mg/die);
14. Antibiotici macrolidici (claritromicina),
15. Sopraggiunta di un evento che porti alla comparsa di un criterio di non selezione.

E.5 End points

E.5.1

Primary end point(s)

HbF level in peripheral blood at day 360 compared to day 0, assessed through HPLC.

Livello di HbF nel sangue periferico al giorno 360 rispetto al giorno 0, valutato mediante HPLC

E.5.1.1

Timepoint(s) of evaluation of this end point

all the study period

tutto il periodo di studio

E.5.2

Secondary end point(s)

- HbF level in peripheral blood at days 10, 90 and 180 compared to day 0, assessed through HPLC.
- Assessment of HbF level as % of HbF with respect to total hemoglobin production in ErPCs at day 90, 180 and 360 compared to day 0,
- Level of induction of the ¿-globin expression at day 90, 180 and 360 compared to day 0
- Haematic analysis and evaluation of the biomarkers for erythropoiesis and haemolysis level at day 180 and 360 compared to baseline. Biomarkers will be: reticulocytes count, nucleated red blood cells (NRBCs), serum lactate dehydrogenase (LDH), serum bilirubin level, erythropoietin level, serum transferrin receptor level.
- Measurement of the total blood quantity (in mL) transfused and recording of the number of transfusions done in a semester (day -360 to -180, day -180 to 0, day 0 to 180, day 180 to 360)
- Evaluation of the intake of iron chelators at days 180 and 360 compared to baseline
- Evaluation of serum ferritin level at day 90, 180 and 360 in comparison with day 0
- Peripheral blood immunophenotype-Lymphocyte subsets at day 90 and 360 compared to day 0
- Quantitative analysis of IgG/IgA/IgM at day 90 and 360 compared to day 0
- Evaluation of the patient quality of life at 6 and 12 months compared to baseline through TranQoL questionnaire.

- Livello di HbF nel sangue periferico ai giorni 10, 90 e 180 rispetto al giorno 0, valutato mediante HPLC
- Valutazione del livello di HbF come % di HbF rispetto alla produzione totale di emoglobina in ErPCsat ai giorni 90, 180 e 360 rispetto al giorno 0,
- Livello di induzione dell'espressione della ¿-globina al giorno 90, 180 e 360 rispetto al giorno 0
- Analisi ematologiche e valutazione dei biomarcatori per l'eritropoiesi e il livello di emolisi al giorno 180 e 360 rispetto al basale. I biomarcatori saranno: conteggio dei reticolociti, globuli rossi nucleati (NRBC), lattato deidrogenasi sierica (LDH), livello di bilirubina sierica, livello di eritropoietina, livello del recettore della transferrina sierica.
- Misurazione della quantità di sangue totale (in ml) trasfusa e registrazione del numero di trasfusioni effettuate in un semestre (dal giorno -360 al -180, dal giorno -180 al 0, dal giorno 0 al 180, dal giorno 180 al 360)
- Valutazione dell'assunzione di chelanti del ferro nei giorni 180 e 360 rispetto al basale
- Valutazione del livello di ferritina sierica al giorno 90, 180 e 360 rispetto al giorno 0
- Valutazione dal sangue periferico di sottogruppi di immunofenotipi di linfociti al giorno 90 e 360 rispetto al giorno 0
- Analisi quantitativa di IgG/IgA/IgM ai giorni 90 e 360 rispetto al giorno 0
- Valutazione della qualità della vita del paziente a 6 e 12 mesi rispetto al basale attraverso il questionario TranQoL.

E.5.2.1

Timepoint(s) of evaluation of this end point

all the study period

tutto il periodo di studio

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

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

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

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

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

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)

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)

At the end of the study, patients will be treated as normal clinical practice

Alla fine dello studio i pazienti verranno trattati come da normale pratica clinica

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

2019-04-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-17

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

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