Clinical Trials Register

Summary
EudraCT Number:	2020-004840-27
Sponsor's Protocol Code Number:	BO42452
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:	2021-06-08
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

2020-004840-27

A.3

Full title of the trial

A PHASE IB RANDOMIZED, PLACEBO-CONTROLLED STUDY EVALUATING THE SAFETY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF CROVALIMAB FOR THE MANAGEMENT OF ACUTE UNCOMPLICATED VASO-OCCLUSIVE EPISODES (VOE) IN PATIENTS WITH SICKLE CELL DISEASE (SCD)

STUDIO DI FASE IB, RANDOMIZZATO E CONTROLLATO VERSO PLACEBO, VOLTO A VALUTARE LA SICUREZZA, LA FARMACOCINETICA, LA FARMACODINAMICA E L’EFFICACIA DI CROVALIMAB PER LA GESTIONE DI EPISODI VASO-OCCLUSIVI ACUTI SENZA COMPLICANZE IN PAZIENTI AFFETTI DA ANEMIA A CELLULE FALCIFORMI O SICKLE CELL DISEASE (SCD)

A.3.1

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

A Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Crovalimab for the Management of Acute Uncomplicated Vaso-Occlusive Episodes in Patients with Sickle Cell Disease

STUDIO VOLTO A VALUTARE LA SICUREZZA, LA FARMACOCINETICA, LA FARMACODINAMICA E L’EFFICACIA DI CROVALIMAB PER LA GESTIONE DI EPISODI VASO-OCCLUSIVI ACUTI SENZA COMPLICANZE IN PAZIENTI AFFETTI DA ANEMIA A CELLULE FALCIFORMI O SICKLE CELL DISEASE (SCD)

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

BO42452

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	F. HOFFMANN - LA ROCHE LTD.
B.1.3.4	Country	Switzerland
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	F.Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F.Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4047
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	000000
B.5.5	Fax number	000000
B.5.6	E-mail	global.rochegenentechtrials@roche.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	Crovalimab
D.3.2	Product code	[RO7112689/F03-10]
D.3.4	Pharmaceutical form	Solution for injection/infusion
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	CROVALIMAB
D.3.9.2	Current sponsor code	RO7112689
D.3.9.3	Other descriptive name	C5 inh MAb, SKY59, RO/CH7092230
D.3.9.4	EV Substance Code	SUB197998
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	170
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Sickle cell disease (SCD); vaso-occlusive episodes (VOE) in SCD

Anemia a cellule falciformi o sickle cell disease (SCD); episodi vaso-occlusivi (Vaso-Occlusive Episode, VOE) acuti senza complicanze

E.1.1.1

Medical condition in easily understood language

Sickle cell disease is an inherited red blood cell disorder that affects hemoglobin and leads to painful episodes (also known as vaso-occlusive episodes [VOE]).

L'anemia falciforme è una malattia ereditaria dei globuli rossi che colpisce l'emoglobina e porta a episodi dolorosi (noti anche come episodi vaso-occlusivi [VOE]).

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10040644
E.1.2	Term	Sickle cell disease
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	LLT
E.1.2	Classification code	10072397
E.1.2	Term	Vaso-occlusive crisis
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To evaluate the safety of crovalimab compared with placebo

Valutare la sicurezza di crovalimab rispetto al placebo

E.2.2

Secondary objectives of the trial

• To evaluate the pharmacokinetics (PK) of crovalimab
• To evaluate the pharmacodynamics (PD) of crovalimab
• To evaluate the efficacy of crovalimab compared with placebo
• To evaluate the immune response to crovalimab

-caratterizzare il profilo farmacocinetico di crovalimab
-nel valutare i biomarcatori farmacodinamici che sono in grado di fornire evidenze sull’attività di crovalimab
-caratterizzare l’efficacia di crovalimab
-valutare la risposta immunitaria a crovalimab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Signed ICF or Assent Form (as determined by patient’s age and individual site and country standards)
• Age >=12 to =<55 years
• Body weight >=40 kg
• Confirmed diagnosis of HbSS (SCD genotype of sickle cell anemia) or HbSß0 (SCD genotype of sickle cell beta zero thalassemia)
• Vaccination against Neisseria meningitidis
• Vaccinations against H. influenzae type B and S. pneumoniae
• Diagnosis of an acute uncomplicated VOE, that requires admission to a hospital/acute medical facility and treatment with parenteral opioid analgesics
• Adequate hepatic and renal function
• Hemoglobin >=5 g/dL
• Platelet count >=100,000/µL
• Patients receiving sickle cell therapies must be on a stable dose for >=28 days
• For female patients of childbearing potential, an agreement to remain abstinent or use contraception for 6 months after the dose of study treatment

-Sottoscrizione del consenso informato principale (ICF) o del modulo di assenso (come stabilito dall’età del paziente, dal singolo centro di sperimentazione e dalle normative nazionali).
-Età =12 e =55 anni
-Peso corporeo =40 kg
-Diagnosi confermata di HbSS o HbSß0
-Vaccinazione contro Neisseria meningitidis
-Vaccinazioni contro Haemophilus influenzae di tipo B e Streptococcus pneumoniae
-Diagnosi di VOE acuto senza complicanze che richiede il ricovero in ospedale/struttura di assistenza acuta e il trattamento con analgesici oppioidi per via parenterale.
-Adeguata funzionalità epatica e renale
-Emoglobina >=5 g/dL
-Conta piastrinica >=100,000/µL
-Assunzione di terapie per la SCD a dosi stabili per >=28 giorni
-Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o a fare uso di metodi contraccettivi per i 6 mesi successivi all'ultima dose di farmaco

E.4

Principal exclusion criteria

• More than 10 VOEs within the last 12 months prior to presentation, that have required a medical facility visit
• Pain related to the current VOE ongoing for >48 hours
• Acute pain related to avascular necrosis, hepatic or splenic sequestration, or priapism
• Pain atypical of an acute uncomplicated VOE
• Evidence of or suspicion of ACS
• Evidence or high suspicion of a severe systemic infection
• Major surgery and/or hospitalization for any reason within 30 days
• History of Neisseria meningitidis infection within 6 months prior
• Known HIV infection with a documented CD4 count <200 cells/µL
• Transfusion or receipt of blood products within 3 months or current participation in a chronic transfusion protocol
• Immunized with a live attenuated vaccine within 30 days
• History of hematopoietic stem cell transplant
• Known or suspected hereditary complement deficiency
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 6 months after the study drug administration
• Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within the prior 28 days or within five half-lives of that investigational product, whichever was greater

-Manifestazione di oltre 10 VOE negli ultimi 12 mesi precedenti la presentazione, che hanno richiesto una visita presso una struttura sanitaria
-Dolore correlato al VOE in atto che persiste per >48 ore prima della presentazione per VOE.
-Dolore acuto correlato a necrosi avascolare (laddove la presenza di dolore risulti circoscritta all’articolazione interessata), sequestro epatico o splenico, o priapismo
-Dolore atipico associato a un VOE acuto senza complicanze
-Evidenza o sospetto di ACS
-Evidenza o forte sospetto di infezione sistemica grave
-Procedura chirurgica maggiore e/o ricovero ospedaliero per qualsiasi motivo nei 30 giorni precedenti la presentazione per VOE
-Positività anamnestica per infezione da N. meningitidis nei 6 mesi precedenti la presentazione per VOE
-Presenza nota di infezione da HIV, con conta CD4 documentata <200 cellule/µl
-Emotrasfusione o assunzione di emoderivati nei 3 mesi precedenti oppure attuale partecipazione a un protocollo trasfusionale cronico
-Immunizzazione con un vaccino vivo attenuato nei 30 giorni precedenti
-Positività anamnestica per trapianto di cellule staminali ematopoietiche
-Presenza nota o sospetto di deficienza del complemento ereditaria
-Gravidanza o allattamento o intenzione di iniziare una gravidanza durante lo studio o nei 6 mesi successivi alla somministrazione del farmaco in studio
-Partecipazione a un altro studio clinico interventistico su un farmaco sperimentale oppure uso di qualsiasi trattamento sperimentale nei 28 giorni precedenti la presentazione per VOE o nelle cinque emivite del farmaco sperimentale, dei due il periodo più lungo

E.5 End points

E.5.1

Primary end point(s)

1. Incidence and severity of adverse events, with severity determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE v5.0)
2. Change from baseline in targeted vital signs and clinical laboratory test results
3. Incidence and severity of infusion-related reactions and hypersensitivity

1. incidenza e severità degli eventi avversi, con grado di severità determinato utilizzando i criteri comuni di terminologia per gli eventi avversi del National Cancer Institute (NCI Common Terminology Criteria for Adverse Events), versione 5.0 (NCI CTCAE v5.0);
2. variazione, rispetto al basale, dei segni vitali mirati e dei risultati di test clinici di laboratorio mirati;
3. incidenza e severità delle reazioni correlate all’infusione e da ipersensibilità.

E.5.1.1

Timepoint(s) of evaluation of this end point

1-3. Up to 84 days

1-3 fino a 84 giorni

E.5.2

Secondary end point(s)

1. Serum concentrations of crovalimab over time
2. Relationships between drug exposure and pharmacodynamics, efficacy or safety endpoints of crovalimab
3. Change over time in PD markers (CH50, free C5, sC5b-9)
4. Time to improvement of the primary acute uncomplicated VOE from baseline
5. Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study

1. concentrazioni sieriche di crovalimab nel corso del tempo
2. correlazioni tra l’esposizione al farmaco e gli endpoint di farmacodinamica, efficacia o sicurezza relativi a crovalimab
3. variazione, nel corso del tempo, dei biomarcatori farmacodinamici (CH50, free C5, sC5b-9)
4. tempo al miglioramento, rispetto al basale, del VOE primario acuto senza complicanze
5. prevalenza degli anticorpi antifarmaco (Anti-Drug Antibody, ADA) al basale e incidenza degli ADA durante lo studio (pazienti randomizzati a crovalimab)

E.5.2.1

Timepoint(s) of evaluation of this end point

1-3. Baseline to Day 84
4. Baseline to hospital discharge (up to 84 days)
5. Baseline to Day 84

1-3. dal baseline al giorno 84
4. dal basale alla dimissione (fino a 84 giorni)
5. dal baseline al giorno 84

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase IB

Fase IB

E.7.2

Therapeutic exploratory (Phase II)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

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

Brazil

United States

France

Italy

Spain

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 or the date at which the last data point is received from the last patient on study, whichever occurs later.

La conclusione di questo studio corrisponde alla data in cui l’ultimo paziente
restante ha completato l’ultima visita (LPLV) o la data in cui l'ultimo data point viene ricevuto dall'ultimo paziente in studio, a seconda di quale si verifica più tardi.

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)

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)

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

Minors

Minori

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)

Given only a single interventional dose of study treatment for this study, currently the Sponsor does not have any plans to provide Roche IMP (crovalimab) or any other study Crovalimab treatments to patients who have completed the study. The Sponsor may evaluate whether to continue providing crovalimab in accordance with the Roche Global Policy on Continued Access to Investigational medicinal Product: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

Poichè questo studio prevede la somministrazione di una singola dose di trattamento sperimentale, attualmente lo Sponsor non ha in programma di fornire il Roche IMP (crovalimab) o altri trattamenti in studio con Crovalimab ai pazienti che hanno completato lo studio. Lo Sponsor può valutare se continuare a fornire crovalimab in conformità con la Roche Global Policy on Continued Access to Investigational Medicines Product

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

2021-06-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-19

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

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