Clinical Trials Register

Summary
EudraCT Number:	2016-002128-10
Sponsor's Protocol Code Number:	BP39144
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2016-10-24
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

Germany - PEI

A.2

EudraCT number

2016-002128-10

A.3

Full title of the trial

An adaptive Phase I/II study to assess safety, efficacy, pharmacokinetics and pharmacodynamics of crovalimab in healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH)

A.3.1

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

A Study to Assess Safety, Effectiveness, Pharmacokinetics, and Pharmacodynamics of crovalimab in Healthy Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria

A.4.1

Sponsor's protocol code number

BP39144

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	4070
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	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.3.2	Product code	RO7112689/F01
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	Not available
D.3.9.1	CAS number	1917321-26-6
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	SUB183839
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.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.3.2	Product code	RO7112689/F03-01
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	Not available
D.3.9.1	CAS number	1917321-26-6
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	SUB183839
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.IMP: 3
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.3.2	Product code	RO7112689/F03-03
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	Not available
D.3.9.1	CAS number	1917321-26-6
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	SUB183839
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
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
D.8 Placebo: 2
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	Subcutaneous use

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

Paroxysmal nocturnal hemoglobinuria is a rare, acquired, life-threatening disease of the blood that leads to the premature death and impaired production of red blood cells

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10055629
E.1.2	Term	Paroxysmal nocturnal hemoglobinuria
E.1.2	System Organ Class	100000004857

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

Part 1
•Evaluate the safety and tolerability of single doses of crovalimab in healthy volunteers (HVs) Part 2, 3 and 4
•Evaluate the safety and tolerability of crovalimab for a total duration of 5 months in treatment naïve patients with PNH and PNH patients
switching treatment to crovalimab
•Evaluate the pharmacodynamic (PD) effect of multiple doses of crovalimab on complement activity in patients with PNH Open Label Extension (OLE)
•Assess the long term safety of crovalimab

E.2.2

Secondary objectives of the trial

Part 1
•Characterize the PD effects of a single-dose of crovalimab on complement activity (CA) & other related biomarkers
•Describe the single-dose pharmacokinetic (PK) profile of crovalimab
•Assess the bioavailability of subcutaneous (SC) administration of crovalimab
Part 2, 3 and 4
•Describe the multiple-dose PK properties of crovalimab in treatment naïve patients (Pts) with PNH and PNH Pts switching treatment to crovalimab
•Characterize other PD effects of crovalimab
•Characterize the exposure-response relationship of crovalimab following different SC dosing regimens
•Assess the efficacy, Pt-related outcomes & treatment satisfaction of crovalimab in treatment naïve Pts with PNH, and/or PNH Pts switching treatment to crovalimab
Parts 1, 2 & 3
•Explore the PK/PD relationship of single-ascending & multiple doses of crovalimab on CA & other related biomarkers
•Evaluate the immunogenicity of crovalimab in HVs and in Pts with PNH OLE
•Assess the long term safety of crovalimab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part 1 (HVs only)
- Healthy male volunteers between the age of 21 and 55 years
- Neisseria meningitidis vaccination against serogroups B and A, C, W, and Y
- Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test result are eligible for the study
- Subjects who have been vaccinated against hepatitis B Parts 2, 3 and 4 (PNH patients only)
- Male or female patients between the age of 18 and 75 years
- Neisseria meningitidis vaccination in accordance with most current local guidelines or Standard of Care (SOC) for patients at increased risk
for meningococcal disease (Part 2 and Part 4 Arm A)
- Patient has been vaccinated with Neisseria meningitidis vaccine(s) in accordance with most current local guidelines or SOC for patients at
increased risk for meningococcal disease or is being revaccinated if applicable (Part 3 and Part 4 Arm B)
- Stable dose for >= 28 days prior to screening of other therapies (immunosuppressant therapy, corticosteroids, iron supplements)
- Negative pregnancy test for women of childbearing potential Part 2 and Part 4 Arm A only (currently untreated PNH patients who are
candidates for treatment with complement inhibitors only):
- Hepatitis B patients can be enrolled if their LFT values are less than 2 × ULN and there is no liver function impairment
- PNH patients who have not been treated with any complement inhibitor or if previously treated stopped treatment due to lack of efficacy based on a single missense C5 heterozygous mutation Part 3 and Part 4 Arm B only (PNH patients currently treated with eculizumab only):
- Subjects with a negative hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody, and HIV test result are eligible for the study.
o Subjects seropositive for HCV but adequately treated without detectable HCV RNA are eligible
o Subjects who have been vaccinated against hepatitis B are eligible
o Subjects seropositive for HBV but adequately treated without detectable HBV DNA are eligible
- Patients are adequately controlled based on investigator opinion
- Patients receive regular infusions of eculizumab OLE only - PNH patients:
- PNH patients who have completed Parts 2, 3 and 4 respectively
- PNH patients who derived, in the Investigator's opinion, benefit from treatment with crovalimab
- For women who are not post menopausal and have not undergone surgical sterilization agreement to remain abstinent or use a contraception method that results in a failure rate of <1% per year, during the treatment period and for 5 half-lives or at least 6 months after the last dose of crovalimab

E.4

Principal exclusion criteria

Parts 1, 2, 3 and 4:
- Known or suspected hereditary complement deficiency
- History of meningococcal meningitis
- Any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 28 days prior to screening or oral antibiotics within 2 weeks prior to screening and up to first study drug administration
- History of or currently active primary or secondary immunodeficiency, including known history of HIV infection
- Evidence of malignant disease including myelodysplastic syndrome, or malignancies diagnosed within the previous 5 years

Part 1 (HVs only):
- Any clinically relevant history or the presence of moderate to severe respiratory, renal, hepatic, gastrointestinal, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, or connective tissue disease
- Any major illness within one month before the screening examination or any febrile illness within 2 weeks prior to screening and up to first study drug Administration
- Prior splenectomy
- History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease
- Congenital or acquired complement deficiency
- Carriers of Neisseria meningitides based on cultures from naso-pharyngeal swabs

Parts 2, 3 and 4 (PNH patients only):
- Evidence of moderate to severe concurrent renal, liver, cardiac, pulmonary or gastrointestinal disease not related to PNH as determined by the Investigator
- History of bone marrow transplantation
- Treatment with azathioprine or erythrocyte-stimulating agents within 14 days prior to first study drug Administration
- Splenectomy < 1 year before start of crovalimab.
Part 3 and 4 Arm B ( PNH patients only):
- Any evidence of sero-positive auto-immune connective tissue
diseases
- Any evidence of active inflammatory conditions

E.5 End points

E.5.1

Primary end point(s)

Safety (Parts 1, 2, 3 and 4):
1. Incidence of dose-limiting events
2. Incidence and severity of adverse events (AEs), serious adverse events and AEs leading to withdrawal
PD (Parts 1, 2, 3 and 4):
3. Ex vivo liposome lysis in serum and ex-vivo lysis of antibody-coated erythrocytes
4. Total and target engaged C5 concentration
5. Serum LDH

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety and PD (Parts 1, 2, 3 and 4):
1-5. Approximately 6 months for Part 1; approximately 8 months for Parts 2 and 3; up to a maximum of five years from entry into OLE

E.5.2

Secondary end point(s)

Efficacy (Parts 2, 3 and 4):
1. Change in LDH
2. Time to (1) first transfusion or (2) persistent elevation of LDH
3. Proportion of patients with LDH below ULN, proportion of patients with LDH <= 1.5 x ULN
4. Change in free-haemoglobin
5. Proportion of patients with stabilized haemoglobin levels
6. Change in fatigue as measured by the functional assessment of chronic illness therapy fatigue
7. Change in health-related quality of life as measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30
8. Comparison of patient treatment satisfaction between IV and SC modes of administration
9. Number of packed RBC (pRBC) units transfused per patient
10. Monthly rate of pRBC transfusions per patient
11. Proportion of transfusion-free patients
12. Annual rate of transfusion avoidance per patient
13. Annual rate of breakthrough hemolysis per patient PK (Parts 1, 2, 3 and 4):
14. Pharmacokinetic profile of crovalimab; Cmax, Tmax, AUC, T1/2, bioavailability following SC administration

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy and PK (Parts 1, 2, 3 and 4):
1-10. Approximately 6 months for Part 1; approximately 8 months for Parts 2, 3 and 4; up to a maximum of five years from entry into OLE

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

Yes

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

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

Yes

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

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

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

France

Germany

Hungary

Italy

Japan

Korea, Republic of

Netherlands

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

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

Yes

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)

The Sponsor will offer post-trial access to the study drug (RO7112689) free of charge to eligible patients, i.e., patients who derive clinical benefit from RO7112689, in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product. Please see section 4.4.4 of the protocol for further information.

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

2017-03-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-14

P. End of Trial
P.	End of Trial Status	Restarted

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IMP with orphan designation in the indication
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