Clinical Trials Register

Summary
EudraCT Number:	2022-003853-70
Sponsor's Protocol Code Number:	PNRR-MR1-2022-12375914
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2023-02-13
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

2022-003853-70

A.3

Full title of the trial

Towards a personalized precision medicine in rare disease: tirzepatide (a dual glucose dependent insulinotropic polypeptide and glucagon-like peptide-I receptor agonist) monotherapy in patients with Wolfrarn syndrome type 1.

Verso una medicina di precisione personalizzata nelle malattie rare: monoterapia con tirzepatide (un doppio agonista del recettore del peptide insulinotropo glucosio-dipendente e del peptide glucagone-simile-I) in pazienti con sindrome di Wolfrarn di tipo 1.

A.3.1

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

Tirzepatide, a new drug for type 2 diabetes mellitus and obesity, as a possible treatment to modify the clinical evolution of Wolfram syndrome type 1

Tirzepatide, un nuovo farmaco per il diabete mellito di tipo 2 e l’obesità, come possibile trattamento per modificare l’evoluzione clinica della sindrome di Wolfram di tipo 1

A.3.2

Name or abbreviated title of the trial where available

Wolfram-Tirzepatide - PNRR-MR1-2022-12375914

A.4.1

Sponsor's protocol code number

PNRR-MR1-2022-12375914

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/311/2019

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	OSPEDALE SAN RAFFAELE
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	PNRR - Ministero della Salute
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS OSPEDALE SAN RAFFAELE
B.5.2	Functional name of contact point	Clinical Trial Center
B.5.3	Address:
B.5.3.1	Street Address	Via Olgettina 57
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0226436102
B.5.5	Fax number	0226432165
B.5.6	E-mail	ctc.trialstartup@hsr.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	MOUNJARO
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly Nederland B.V
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	MOUNJARO - tirzepatide
D.3.2	Product code	[MOUNJARO]
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tirzepatide
D.3.9.1	CAS number	2023788-19-2
D.3.9.2	Current sponsor code	MOUNJARO
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2.5 to 15
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	Yes
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

Wolfram syndrome type 1

Sindrome di Wolfram tipo 1

E.1.1.1

Medical condition in easily understood language

Diabetes mellitus, optic nerve atrophy, sensorineural deafness, diabetes insipidus, and neurodegeneration in variable combination with poor prognosis

Diabete mellito, atrofia dei nervi ottici, sordità neurosensoriale, diabete insipido e neurodegenerazione in combinazione variabilie e a prognosi infausta

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

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	10078338
E.1.2	Term	Wolfram syndrome
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	10078338
E.1.2	Term	Wolfram syndrome
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	10078338
E.1.2	Term	Wolfram syndrome
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 efficacy of tirzepatide in increasing endogenous insulin production in patients with Wolfram syndrome type 1 (WS1)

Determinare l'efficacia della tirzepatide nell'aumentare la produzione endogena di insulina in pazienti con sindrome di Wolfram di tipo 1 (WS1)

E.2.2

Secondary objectives of the trial

To determine the efficacy of tirzepatide in correcting glycemic lability in Wolfram syndrome type 1

Determinare l'efficacia della tirzepatide nel correggere la labilità glicemica nella sindrome di Wolfram di tipo 1

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Title: "Induced pluripotent stem cells (iPSCs) from patients with Wolfram syndrome Type 1 as a model for predicting response to tirzepatide treatment"
The main objective of this sub-study is the generation of induced pluripotent stem cell (iPSC) lines from peripheral blood of 10 Wolfram syndrome Type 1 (WS1) patients recruited in the phase II interventional study entitled "Towards a personalized precision medicine in rare disease: tirzepatide (a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist) monotherapy in patients with Wolfram syndrome type 1." iPSCs derived from WS1 patients will be differentiated into ß cells, and the basic characteristics and functional properties of ß cells treated or not treated with tirzepatide will be examined. A correlation analysis will then be performed between the cellular and patient response to tirzepatide

Translated with www.DeepL.com/Translator (free version)

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Titolo: "Cellule staminali pluripotenti indotte (iPSC) da pazienti con sindrome di Wolfram di tipo 1 come modello per prevedere la risposta al trattamento con tirzepatide"
L’obiettivo principale di questo sotto studio è la generazione di linee di cellule staminali pluripotenti indotte (iPSC) a partire da sangue periferico di 10 pazienti affetti da sindrome di Wolfram di Tipo 1 (WS1) reclutati nello studio interventistico di fase II dal titolo “Towards a personalized precision medicine in rare disease: tirzepatide (a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist) monotherapy in patients with Wolfram syndrome type 1”. Le iPSC derivate dai pazienti WS1 verranno differenziate in cellule ß e verranno esaminate le caratteristiche di base e le proprietà funzionali delle cellule ß trattate o meno con tirzepatide. Verrà poi effettuata un’analisi di correlazione fra la risposta cellulare e quella del paziente a tirzepatide

E.3

Principal inclusion criteria

1) A definite diagnosis of Wolfram syndrome, as determined by the following:
(a) Documented diabetes mellitus diagnosed under 16 years of age according to WHO or ADA criteria; and
(b) Documented functionally relevant recessive mutations on both alleles of the WFS1 gene or dominant mutation on one allele of the WFS1 gene based on historical test results (if available) or from a qualified screening laboratory;
2) aged 5 years or older;
3) The patient, the patient's parents or legally authorized guardian(s) must have voluntarily signed an informed consent form approved by the Institutional Review Board/Independent Ethics Committee after all relevant aspects of the study have been explained and discussed with the patient . Guardian consent and patient consent, if applicable, must be obtained;
4) Women of childbearing age will be included only after a highly sensitive negative urine pregnancy test. If sexually active, they must agree to use a highly effective contraceptive measure;
5) Patient willing to wear a continuous glucose monitor.

1) Una diagnosi definitiva di sindrome di Wolfram, come determinato da quanto segue:
a) Diabete mellito documentato diagnosticato sotto i 16 anni compiuti secondo i criteri OMS o ADA e
b) Mutazioni recessive funzionalmente rilevanti documentate su entrambi gli alleli del gene WFS1 o mutazione dominante su un allele del gene WFS1 sulla base dei risultati dei test storici (se disponibili) o da un laboratorio qualificato allo screening;
2) di età pari o superiore a 5 anni;
3) Il paziente, i genitori del paziente o il/i tutore/i legalmente autorizzato/i devono aver firmato volontariamente un modulo di consenso informato approvato dall'Institutional Review Board/Comitato etico indipendente dopo che tutti gli aspetti rilevanti dello studio sono stati spiegati e discussi con il paziente . Il consenso dei tutori e il consenso del paziente, se del caso, devono essere ottenuti;
4) Le donne in età fertile saranno incluse solo dopo un test di gravidanza sulle urine altamente sensibile negativo. Se sessualmente attivi, devono accettare di utilizzare una misura contraccettiva altamente efficace;
5) Paziente disposto a indossare un monitor continuo del glucosio.

E.4

Principal exclusion criteria

1) Clinically significant CNS involvement unrelated to Wolfram that is judged by the investigator likely to interfere with the accurate administration and interpretation of protocol assessments;
2) A history of pancreatitis;
3) Pre-existing thyroid disease;
4) A personal or family history of medullary thyroid carcinoma;
5) Multiple endocrine neoplasia type 2 syndrome;
6) Active liver or kidney disease, personal or family history of liver/renal dysfunction related to known genetic disease;
7) Treatment with any investigational drug within 30 days prior to study entry;
8) Ongoing therapy with a GLP-1 agonist or DDP-4 inhibitor or known hypersensitivity to the GLP-1 agonist;
9) Any other medical, psychiatric, social situation or acute or chronic laboratory outcome that, in the judgment of the investigator, would jeopardize the safety of the patient while participating in the study, cause inability to comply with the protocol, or affect the outcome of the study;
10) Breastfeeding;
11) Pre-existing eye disease (corneal or lens disease and any other retinal or optic nerve disease not related to Wolfram).

1) Coinvolgimento del SNC clinicamente significativo non correlato a Wolfram che è giudicato dallo sperimentatore probabile che interferisca con l'accurata somministrazione e interpretazione delle valutazioni del protocollo;
2) Una storia di pancreatite;
3) Malattia tiroidea preesistente;
4) Una storia personale o familiare di carcinoma midollare della tiroide;
5) Sindrome da neoplasia endocrina multipla di tipo 2;
6) Malattia epatica o renale attiva, anamnesi personale o familiare di disfunzione epatica/renale correlata a malattie genetiche note;
7) Trattamento con qualsiasi farmaco sperimentale nei 30 giorni precedenti l'ingresso nello studio;
8) Terapia in corso con un agonista del GLP-1 o un inibitore del DDP-4 o ipersensibilità nota all'agonista del GLP-1;
9) Qualsiasi altra situazione medica, psichiatrica, sociale o risultato di laboratorio acuto o cronico che, in base al giudizio dello sperimentatore, metterebbe a repentaglio la sicurezza del paziente durante la partecipazione allo studio, causerebbe l'impossibilità di rispettare il protocollo o influire sull'esito dello studio;
10) Allattamento al seno;
11) Malattie oculari preesistenti (malattie della cornea o del cristallino e qualsiasi altra malattia della retina o del nervo ottico non correlata a Wolfram).

E.5 End points

E.5.1

Primary end point(s)

The percentage of participants with a positive response to MMTT (C-peptide at 90 min >0.6 ng/ml)

La percentuale di partecipanti con una risposta positiva all'MMTT (C-peptide a 90 min >0,6 ng/ml)

E.5.1.1

Timepoint(s) of evaluation of this end point

6 and 12 months after start of treatment

Dopo 6 e 12 mesi dal trattamento

E.5.2

Secondary end point(s)

Glucometrics (time in-above-below range, mean/5D, GMI), HbAlc, depending.

Glucometria (tempo di permanenza nell'intervallo superiore/inferiore, media/5D, GMI), HbAlc.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, 6 months, 12 months

Al baseline, a 6 mesi e a 12 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

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

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

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

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

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.1.1.1

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)

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children and patients with neurological impairment

Bambini e pazienti con ritardo neurologico

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)

Patients will follow the standard follow-up expected for the disease as per international guidelines.

I pazienti seguiranno il follow-up standard previsto per la malattia come da linee guida internazionali.

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

2023-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-03-15

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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