Clinical Trials Register

Summary
EudraCT Number:	2021-001671-16
Sponsor's Protocol Code Number:	ACT17209
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:	2021-10-12
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

2021-001671-16

A.3

Full title of the trial

A multicenter, open-label, Phase IIb study to evaluate the efficacy, safety and pharmacokinetics of rilzabrutinib in patients with warm autoimmune hemolytic anemia

Studio multicentrico, in aperto, di Fase IIb per valutare l’efficacia, la sicurezza e la farmacocinetica di rilzabrutinib in pazienti con anemia emolitica autoimmune calda

A.3.1

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

Efficacy, safety and pharmacokinetics of rilzabrutinib in patients with warm
autoimmune hemolytic anemia

Efficacia, sicurezza e farmacocinetica di rilzabrutinib in pazienti con anemia emolitica autoimmune calda

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

ACT17209

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1262-2929

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	SANOFI-AVENTIS RECHERCHE E DEVELOPPEMENT
B.1.3.4	Country	France
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	Sanofi Aventis Recherche et Developpement
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SANOFI S.r.l.
B.5.2	Functional name of contact point	CONTACT POINT
B.5.3	Address:
B.5.3.1	Street Address	VIALE LUIGI BODIO 37/B
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20158
B.5.3.4	Country	Italy
B.5.4	Telephone number	800226343
B.5.5	Fax number	0239394168
B.5.6	E-mail	informazioni.medicoscientifiche@sanofi.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rilzabrutinib
D.3.2	Product code	[SAR444671]
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	Rilzabrutinib
D.3.9.2	Current sponsor code	SAR444671
D.3.9.3	Other descriptive name	PRN1008
D.3.9.4	EV Substance Code	SUB192772
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	400
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

Warm autoimmune hemolytic anemia

anemia emolitica autoimmune calda

E.1.1.1

Medical condition in easily understood language

Warm autoimmune hemolytic anemia

anemia emolitica autoimmune calda

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10073785
E.1.2	Term	Autoimmune haemolytic anaemia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part A: To evaluate the efficacy of rilzabrutinib in adult patients with wAIHA
Part B: To evaluate the long-term efficacy of rilzabrutinib in patients with wAIHA

Parte A:
• Valutare l’efficacia di rilzabrutinib in pazienti adulti con wAIHA
Parte B:
• Valutare l’efficacia a lungo termine di rilzabrutinib in pazienti con wAIHA

E.2.2

Secondary objectives of the trial

Part A:
• To evaluate the durable hemoglobin response in adult patients with wAIHA
• To assess time to response (TTR)
Parts A and B:
• To assess the effect of treatment with rilzabrutinib on rescue medication requirement in patients with wAIHA
• To evaluate the impact of rilzabrutinib treatment on fatigue
• To evaluate the safety and tolerability of rilzabrutinib in patients with wAIHA

Parte A:
• Valutare la risposta duratura dell’emoglobina in pazienti adulti con wAIHA.
• Valutare il tempo alla risposta (TTR).
Parti A e B:
Valutare l’effetto del trattamento con rilzabrutinib sulla necessità di farmaci di soccorso in pazienti con wAIHA.
Valutare l’impatto del trattamento con rilzabrutinib sull’affaticamento.
Valutare la sicurezza e la tollerabilità di rilzabrutinib in pazienti con wAIHA.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male and female patients with a confirmed diagnosis of primary wAIHA or systemic lupus erythematosus (SLE)-associated wAIHA (without other SLE-related manifestations apart from cutaneous and musculoskeletal manifestations)
- Participants who have previously failed to maintain a sustained response after treatment with corticosteroids.
- Eastern Cooperative Oncology Group (ECOG) performance status grade 2 or lower.
- Up-to-date vaccination status as per local guidelines.
- Body mass index (BMI) >17.5 and <40 kg/m2
- All contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Part B only
- Evidence of treatment efficacy to rilzabrutinib as defined by achieving overall response during Part A.
- Completion of Part A treatment period (24 weeks).

Pazienti di sesso maschile e femminile con diagnosi confermata di wAIHA primaria o di wAIHA associata a lupus eritematoso sistemico (LES) (senza altre manifestazioni correlate al LES, a parte le manifestazioni cutanee e muscoloscheletriche)
Partecipanti che non hanno precedentemente mantenuto una risposta sostenuta dopo il trattamento con corticosteroidi
Stato di funzionalità secondo la scala dell’Eastern Cooperative Oncology Group (ECOG) di Grado 2 o inferiore.
Stato di vaccinazione aggiornato secondo le linee guida locali.
Indice di massa corporea (IMC) >17,5 e <40 kg/m2.
Qualsiasi uso di contraccettivi da parte di uomini e donne deve essere in linea con le normative locali riguardanti i metodi di contraccezione per coloro che partecipano agli studi clinici.
Solo Parte B
Evidenza di efficacia del trattamento con rilzabrutinib definita dal raggiungimento della risposta complessiva durante la Parte A.
Completamento del periodo di trattamento della Parte A (24 settimane).

E.4

Principal exclusion criteria

- Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the participant or compromise the quality of the data derived from his or her participation in the study as determined by the Investigator.
- Participants with medical history of lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for the past 3 years.
- Secondary wAIHA from any cause including drugs, lymphoproliferative disorders (low-count monoclonal B-cell lymphocytosis is allowed), infectious or autoimmune disease, or active hematologic malignancies.
Participants with positive antinuclear antibodies but without a definitive diagnosis of an autoimmune disease are allowed.
- Myelodysplastic syndrome.
- Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA.
- HIV infection.
- Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days or 5 half-lives, whichever is greater, prior to treatment start.
- Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
Part B only
- Participants who receive any therapy during Part A known to be active in wAIHA.
- Presence of unacceptable side effect(s) or toxicity associated with rilzabrutinib such that there is an unfavorable risk-benefit assessment for continued treatment with rilzabrutinib in the opinion of the Investigator and/or Sponsor.

Anamnesi medica clinicamente significativa o malattia cronica in corso che comprometterebbe la sicurezza del partecipante o comprometterebbe la qualità dei dati derivati dalla sua partecipazione allo studio, come stabilito dallo sperimentatore.
Partecipanti con anamnesi medica di linfoma, leucemia o qualsiasi tumore maligno negli ultimi 5 anni, a eccezione dei carcinomi epiteliali basocellulari o squamocellulari che sono stati resecati senza evidenza di malattia metastatica negli ultimi 3 anni.
La wAIHA secondaria per qualsiasi causa, compresi farmaci, disturbi linfoproliferativi (è consentita la linfocitosi monoclonale dei linfociti B a basso conteggio), malattia infettiva o autoimmune o tumori maligni ematologici attivi.
Sono consentiti i partecipanti con anticorpi antinucleari positivi, ma senza diagnosi definitiva di malattia autoimmune.
Sindrome mielodisplastica.
Infezione da HBV non controllata o attiva: pazienti con positività a HBsAg e/o HBV-DNA.
Infezione da HIV
Trattamento concomitante con altri farmaci sperimentali o partecipazione a un’altra sperimentazione clinica con qualsiasi farmaco sperimentale entro 30 giorni o 5 emivite, a seconda di quale sia maggiore, prima dell’inizio del trattamento.
Allergia nota a eventuali farmaci dello studio, loro analoghi o eccipienti nelle varie formulazioni di qualsiasi agente.
Solo Parte B
Partecipanti che ricevono qualsiasi terapia durante la Parte A di cui è nota l’attività contro la wAIHA
Presenza di uno o più effetti collaterali inaccettabili o tossicità associata a rilzabrutinib tale da indurre una valutazione sfavorevole del rapporto rischio-beneficio per il trattamento continuato con rilzabrutinib a giudizio dello sperimentatore e/o dello sponsor.

E.5 End points

E.5.1

Primary end point(s)

1 - Proportion of participants with overall hemoglobin response ;
Response is defined as an increase in hemoglobin (Hb) by >/= 2 g/dL from baseline and an absence of transfusion in the last 7 days, without biochemical resolution of hemolysis at the time response is achieved and an absence of rescue medications during the last 4 weeks.
Complete Response is defined as hemoglobin >/= 11 g/dL (women) or >/=12 g/dL (men), no evidence of hemolysis (normal bilirubin, LDH, haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and an absence of rescue medications during the last 4 weeks.
2 - Proportion of participants who maintain durable response achieved during Part A or achieve a durable response during Part B and have a hemoglobin response ; Durable response (Part B) is defined as Hb level >/=10 g/dL with an increase from baseline (Part A) of >/=2 g/dL on three consecutive scheduled visits during Week 24 to Week 50; with absence of transfusion and no rescue medication during the period of 3 consecutive visits and for at least 7 days (transfusions) and 4 weeks (rescue medication) prior to the first consecutive visit.

Percentuale di partecipanti con risposta complessiva dell’emoglobina
La risposta è definita come un aumento dell’emoglobina (Hb) >/= 2 g/dl rispetto al basale e un’assenza di trasfusioni negli ultimi 7 giorni, senza risoluzione biochimica dell’emolisi al momento in cui viene raggiunta la risposta e assenza di farmaci di soccorso durante le ultime 4 settimane.
La risposta completa è definita come emoglobina >/=11 g/dl (donne) o >/=12 g/dl (uomini), nessuna evidenza di emolisi (bilirubina normale, lattato deidrogenasi (LDH), aptoglobina e reticolociti) e assenza di trasfusioni negli ultimi 7 giorni e assenza di farmaci di soccorso nelle ultime 4 settimane.
2. Percentuale di partecipanti che mantengono una risposta duratura raggiunta durante la Parte A o che ottengono una risposta duratura durante la Parte B e presentano una risposta emoglobinica;
La risposta duratura (Parte B) è definita come livello di Hb >/=10 g/dl con un aumento rispetto al basale (Parte A) >/=2 g/dl in tre visite programmate consecutive durante il periodo dalla Settimana 24 alla Settimana 50; con assenza di trasfusioni e nessun farmaco di soccorso durante il periodo di 3 visite consecutive e per almeno 7 giorni (trasfusioni) e 4 settimane (farmaco di soccorso) prima della prima visita consecutiva

E.5.1.1

Timepoint(s) of evaluation of this end point

1 - By Week 24 in Part A
2 - At Week 50 in Part B

1. Dalla settimana 24 nella parte A
2. Alla settimana 50 nella parte B

E.5.2

Secondary end point(s)

1 - Proportion of participants with durable hemoglobin response ;
Durable response (Part A) is defined as Hb level >/= 10 g/dL with an increase from baseline of >/=2 g/dL on three consecutive evaluable visits during the 24-week treatment period; with absence of transfusion and no rescue medication during the period of 3 consecutive visits and for at least 7 days (transfusions) and 4 weeks (rescue medication) prior to the first consecutive visit.
2 - Median time from baseline to first hemoglobin response
3 - Frequency of rescue therapy (any wAIHA-directed therapy other than predniso[lo]ne or transfusion) received
4 - Change from baseline in FACIT-Fatigue scale score
5 - Safety assessments

1. Percentuale di partecipanti con risposta emoglobinica duratura
La risposta duratura (Parte A) è definita come livello di Hb >/=10 g/dl con un aumento rispetto al basale di >/= 2 g/dl in tre visite valutabili consecutive durante il periodo di trattamento di 24 settimane; con assenza di trasfusione e nessun farmaco di soccorso durante il periodo di 3 visite consecutive e per almeno 7 giorni (trasfusioni) e 4 settimane (farmaco di soccorso) prima della prima visita consecutiva.
2. Tempo mediano dal basale alla prima risposta dell’emoglobina.
3. Frequenza della terapia di salvataggio (qualsiasi terapia diretta contro la wAIHA diversa da predniso[lo]ne o trasfusione) ricevuta
4. Variazione rispetto al basale nel punteggio della scala di Valutazione funzionale della terapia delle malattie croniche-affaticamento (FACIT-Fatigue)
5. valutazioni di sicurezza

E.5.2.1

Timepoint(s) of evaluation of this end point

1 - By Week 24 in Part A
2 - From Day 1 to Week 24 in Part A
3 - After Week 1 of treatment to Week 24 in Part A and Week 75 in Part B
4, 5 - Until Week 24 in Part A and Week 75 in Part B

1 - Entro la settimana 24 nella parte A
2 - Dal giorno 1 alla settimana 24 nella parte A
3 - Dopo la settimana 1 di trattamento alla settimana 24 nella parte A e alla settimana 75 nella parte B
4, 5 - Fino alla settimana 24 nella parte A e alla settimana 75 nella parte B

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

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.8.1.7.1

Other trial design description

studio in aperto

open label study

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

Information not present in EudraCT

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

China

United States

Denmark

Italy

Spain

United Kingdom

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)

none

nessuno

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

2021-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-06

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

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