Clinical Trials Register

Summary
EudraCT Number:	2019-004931-21
Sponsor's Protocol Code Number:	BO42162
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-28
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

Portugal - INFARMED

A.2

EudraCT number

2019-004931-21

A.3

Full title of the trial

A PHASE III, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED, MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF CROVALIMAB VERSUS ECULIZUMAB IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) NOT PREVIOUSLY TREATED WITH COMPLEMENT INHIBITORS

A.3.1

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

A Study to Evaluate the Efficacy and Safety of Crovalimab versus Eculizumab in Adult and Adolescent Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) not previously Treated with Complement Inhibitors

A.4.1

Sponsor's protocol code number

BO42162

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/124/2021

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	F. Hoffman-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. Hoffman-La Roche Ltd.
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Chugai Pharmaceutical Co. Ltd.
B.4.2	Country	Japan
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.5.6	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	Yes
D.2.1.1.1	Trade name	Soliris 300 mg concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Alexion Pharmaceuticals, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Concentrate for solution for 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	ECULIZUMAB
D.3.9.1	CAS number	219685-50-4
D.3.9.4	EV Substance Code	SUB25187
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	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	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.IMP: 2
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 Subcutaneous 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.3.9.4	EV Substance Code	SUB197998
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paroxysmal Nocturnal Hemoglobinuria (PNH)

E.1.1.1

Medical condition in easily understood language

PNH is a rare acquired disorder characterized by destruction of red blood cells, blood clots, and impaired renal function

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10055629
E.1.2	Term	Paroxysmal nocturnal hemoglobinuria
E.1.2	System Organ Class	10038359 - Renal and urinary 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 efficacy of crovalimab compared to eculizumab

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of crovalimab compared with eculizumab
• To evaluate the overall safety and tolerability of crovalimab compared to eculizumab
• To evaluate the pharmacokinetics of crovalimab and eculizumab
• To evaluate the immune response to crovalimab
• To identify and/or evaluate biomarkers that can potentially provide evidence of crovalimab and eculizumab activity

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Body weight >= 40 kg
- Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry evaluation of WBCs
- LDH level >=2 x ULN at screening (as per local assessment)
- Vaccination against Neisseria meningitidis serotypes A, C, W and Y < 3 years prior to initiation of study treatment. Vaccination against serotype B should be administered in accordance with the most current local guidelines or SOC, as applicable in patients with complement deficiency. If not previously administered or no longer current, vaccination must be completed no later than one week after the first study drug administration. Vaccination currency with vaccination against serotypes A, C, W, Y and B should be maintained throughout the study, according to local guidelines or standard-of-care as applicable in patients with complement deficiency. In the absence of clear local guidelines for Neisseria meningitidis, the Advisory Committee on Immunization Practices 2020 Guidelines are recommended.
- Platelet count >= 30,000/mm*3 at screening without transfusion support within 7 days of lab testing.
- ANC > 500/micro L at screening
- For female patients of childbearing potential: agreement to remain abstinent or use contraception

Additional Inclusion Criteria for Patients in the Randomized Arms
-Age >=18 years
Additional Inclusion Criteria for Patients in the Descriptive Arm
- Age < 18 years

E.4

Principal exclusion criteria

- Current or previous treatment with a complement inhibitor
- History of allogeneic bone marrow transplantation
- History of Neisseria meningitidis infection within 6 months prior to
screening and up to first study drug administration
- History of myelodysplastic syndrome with Revised International
Prognostic Scoring System (IPSS-R) prognostic risk categories of
intermediate, high and very high
-Pregnant or breastfeeding, or intending to become pregnant during
the study or within 46 weeks (approximately 10.5 months) after the final dose of crovalimab, or 3
months after final dose of eculizumab (or longer if required by the local
product label)
- Concurrent disease, treatment, procedure, or surgery or abnormality in
clinical laboratory tests that could interfere with the conduct of the
study, may pose any additional risk for the patient, or would, in the
opinion of the Investigator, preclude the patient's safe participation in
and completion of the study
- Splenectomy <= 6 months prior to screening
- Positive for hepatitis B surface antigen at screening
- Positive for hepatitis C virus antibody at screening (confirmed by
detectable viral RNA)
- History of or ongoing cryoglobulinemia at screening

E.5 End points

E.5.1

Primary end point(s)

1. Proportion of patients who achieve transfusion avoidance
2. Proportion of patients with hemolysis control, measured by LDH <=1.5×ULN

E.5.1.1

Timepoint(s) of evaluation of this end point

1. From Baseline to Week 25
2. From Week 5 to Week 25

E.5.2

Secondary end point(s)

1. Proportion of patients with breakthrough hemolysis
2. Proportion of patients with stabilization of hemoglobin
3. Mean change in fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue
4. Incidence and severity of adverse events
5. Change from baseline in targeted vital signs
6. Change from baseline in targeted clinical laboratory test results
7. Incidence and severity of injection-site reactions, infusion-related reactions, hypersensitivity, and infections
8. Incidence of adverse events leading to study drug discontinuation
9. Incidence and severity of clinical manifestations of drug-target-drug complex formation in patients who switched to crovalimab treatment from eculizumab treatment
10. Serum concentration of crovalimab and eculizumab
11. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab
12. Change over time in pharmacodynamic biomarkers
13. Change over time in free C5 concentration in crovalimab-treated patients
14. Observed value and absolute change from baseline to Week 25 in parameters reflecting hemolysis

E.5.2.1

Timepoint(s) of evaluation of this end point

1-3. From baseline to Week 25
4-9. Up to 7 years
10. Up to 7 years (crovalimab) and up to Week 25 (eculizumab)
11. At baseline (prevalence) and up to 7 years (incidence)
12-13. Up to 7 years
14. From baseline to Week 25

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity Objectives:
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study
Biomarker Objective:
To identify and/or evaluate biomarkers that can potentially provide evidence of crovalimab and eculizumab activity

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

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)

Yes

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

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

Argentina

Colombia

Malaysia

Peru

Philippines

Hong Kong

Taiwan

Australia

Brazil

Canada

China

Israel

Japan

Korea, Republic of

Mexico

South Africa

Thailand

United Kingdom

United States

Austria

Belgium

Czechia

France

Germany

Greece

Hungary

Ireland

Italy

Netherlands

Poland

Portugal

Romania

Spain

Sweden

Türkiye

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

LPLV for the last remaining patients as follow:
Crova treatment; Completion of 24 weeks of crovalimab treatment and either transfer to a separate OLE study or continuation per Roche Policy
Ecu treatment: Completion of 24 weeks of study treatment and optional subsequent switch to crovalimab treatment on the study, followed by either transfer to a separate crovalimab OLE study or continuation per Roche Policy
Discontinuation prior to completion of last treatment

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

F.1.2.1

Number of subjects for this age range:

160

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Minors

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

100

F.4.2.2

In the whole clinical trial

200

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)

The Sponsor will offer continued access to Roche IMP (crovalimab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, as outlined in the section 4.3.5 of the protocol

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

2021-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-09

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

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