Clinical Trials Register

Summary
EudraCT Number:	2017-001746-10
Sponsor's Protocol Code Number:	CSEG101A2301
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-05-10
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

Greece - EOF

A.2

EudraCT number

2017-001746-10

A.3

Full title of the trial

A phase III, Multicenter, Randomized, Double-blind Study to Assess Efficacy and Safety of Two Doses of
Crizanlizumab versus placebo, with or without Hydroxyurea/ Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients with Vaso-Occlusive Crises (STAND)

Φάσης ΙΙΙ, πολυκεντρική, τυχαιοποιημένη, διπλά τυφλή μελέτη για την εκτίμηση της αποτελεσματικότητας και της ασφάλειας δύο δόσεων
crizanlizumab έναντι του εικονικού φαρμάκου, με ή χωρίς θεραπεία με υδροξυουρία/υδροξυκαρβαμίδη, σε εφήβους και ενήλικες ασθενείς με ρεπανοκυτταρική νόσο και αγγειοαποφρακτικές κρίσεις (STAND)

A.3.1

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

Study of two doses of crizanlizumab versus placebo in adolescent and adult sickle cell disease patients

A.3.2

Name or abbreviated title of the trial where available

STAND

A.4.1

Sponsor's protocol code number

CSEG101A2301

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03814746

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	Novartis Pharma AG
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	Novartis Pharma AG
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	Novartis (Hellas) S.A.C.I.
B.5.2	Functional name of contact point	Veronique Schaaf
B.5.3	Address:
B.5.3.1	Street Address	12th Klm National Road Athens-Lamia, No1
B.5.3.2	Town/ city	Metamorfosi, Athens
B.5.3.3	Post code	14451
B.5.3.4	Country	Greece
B.5.4	Telephone number	0030 210 2897152
B.5.5	Fax number	0030 210 2835053
B.5.6	E-mail	veronique.schaaf@novartis.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/12/1034
D.3 Description of the IMP
D.3.1	Product name	crizanlizumab
D.3.2	Product code	SEG101
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	CRIZANLIZUMAB
D.3.9.2	Current sponsor code	SEG101
D.3.9.4	EV Substance Code	SUB188615
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.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	Concentrate for solution for 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 with vaso-occlusive crisis

E.1.1.1

Medical condition in easily understood language

Sickle Cell Disease

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10002077
E.1.2	Term	Anaemia sickle cell
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 compare the efficacy of 7.5 mg/kg of
crizanlizumab versus placebo on the annualized rate of VOC leading to healthcare visit, in addition to standard of care
- To compare the efficacy of 5.0 mg/kg of
crizanlizumab versus placebo on the annualized rate of VOC leading to healthcare visit, in addition to standard of care

E.2.2

Secondary objectives of the trial

Key secondary:
- Compare the efficacy of 7.5 mg/kg vs placebo on the annualized rate of all VOCs (managed at home + leading to healthcare visit)
- Compare the efficacy of 5.0 mg/kg vs placebo on the annualized rate of all VOC (managed at home + leading to healthcare visit)
-Assess the time to first and second VOC leading to healthcare visit in
each group
- Assess the annualized rate of VOCs managed at home in each group
- Assess the duration of VOCs leading to healthcare visit in each group
- Assess rate of participants free from VOC leading to healthcare visit in
each group
- Healthcare resource utilization (visits to clinic, Emergency room (ER)
and hospitalizations) in each group vs placebo
- Assess SCD-related renal damage in each group
- Characterize PK profile of SEG101 at 5.0 and 7.5 mg/kg
- Characterize PD (P-selectin inhibition) of SEG101 at 5.0 and 7.5 mg/kg
- Assess efficacy, safety and immunogenicity of SEG101 over study
period (treatment of 5y+105d follow-up)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent must be obtained prior
to any screening procedures
2. Male or female patients aged 12 years and older on the day of signing informed consent. Adolescent include patients aged 12 to 17 years old and adults ≥ 18 years
3. Confirmed diagnosis of SCD by hemoglobin electrophoresis or high performance liquid chromatography (HPLC) [performed locally]. All SCD genotypes are eligible, genotyping is not required for study entry
4. Experienced at least 2 VOCs leading to healthcare visit within the 12 months prior to screening visit as determined by medical history. Prior VOC leading to healthcare visit must resolve at least 7 days prior to Week 1 Day 1 and must include:
a. Pain crisis defined as an acute onset of pain for
which there is no other medically determined
explanation other than vaso- occlusion -
b. a visit to a medical facility and/or healthcare
professional,
c. and receipt of oral/parenteral opioids or parenteral nonsteroidal anti-inflammatory drug (NSAID) analgesics.
Acute chest syndrome (ACS), priapism, and hepatic or splenic sequestration will be considered VOC in this study
5. If receiving HU/HC or L-glutamine (local HA approved medicinal
product), must have been receiving the drug for at least 6 months and at a stable dose for at least 3 months prior to Screening visit and plan to continue taking at the same dose and schedule until the participant has reached one year of study treatment
6. Patients must meet the following central laboratory values prior to
Week 1 Day 1. In case of re-sampling needed, local laboratory values are allowed. Refer to Section 8.4.1 for further details:
• Absolute Neutrophil Count ≥1.0 x 109/L
• Platelet count ≥75 x 109/L
• Hemoglobin: for adults (Hb) ≥4.0 g/dL and for
adolescents (Hb) ≥5.5 g/dL
• Glomerular filtration rate ≥ 45 mL/min/1.73 m2
using CKD-EPI formula in adults, and Shwartz formula in adolescents
• Direct (conjugated) bilirubin < 2.0 x ULN
• Alanine transaminase (ALT) < 3.0 x ULN
7. ECOG performance status ≤2.0 for adults and
Karnofsky ≥ 50% for adolescents

E.4

Principal exclusion criteria

1. History of stem cell transplant.
2. Participating in a chronic transfusion program
(pre-planned series of transfusions for prophylactic
purposes) and/or planning on undergoing an
exchange transfusion during the duration of the study; episodic transfusion in response to worsened anemia or VOC is permitted.
3. Contraindication or hypersensitivity to any drug or
metabolites from similar class as study drug or to any excipients of the study drug formulation. History of severe hypersensitivity reaction to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction.
4. Received active treatment on another
investigational trial within 30 days (or 5 half-lives of
that agent, whichever is greater) prior to Screening
visit or plans to participate in another investigational
drug trial.
5. Women of child-bearing potential, defined as all
women physiologically capable of becoming pregnant unless they are using highly effective methods of contraception during dosing and for 15 weeks after stopping treatment.
6. Concurrent severe and/or uncontrolled medical
conditions which, in the opinion of the Investigator,
could cause unacceptable safety risks or compromise participation in the study.
7. History or current diagnosis of ECG abnormalities indicating significant risk of safety such as:
• Concomitant clinically significant cardiac arrhythmias (e.g ventricular tachycardia), and clinically significant second or third degree AV block without a pacemaker
• History of familial long QT syndrome or know
family history of Torsades de Pointes
8. Not able to understand and to comply with study
intructions and requirements.

E.5 End points

E.5.1

Primary end point(s)

Annualized rate of VOC events leading to healthcare visit in each treatment group over the first year post-randomization

E.5.1.1

Timepoint(s) of evaluation of this end point

1 year

E.5.2

Secondary end point(s)

for key secondary:
- Annualized rate of all VOCs leading to healthcare visit and treated at home (based on documentation by health care provider following contact with participant) over the first year post randomization
- The time to first and second VOC calculated respectively as the time
from date of randomization until the first and the second VOC leading to healthcare visit over the first year post randomization
- Annualized rate of VOCs managed at home over the first year post
randomization
- Duration of VOCs leading to healthcare visit over the first year post
randomization
- Number and percentage of participants free from VOCs leading to
healthcare visit in each group over the first year post randomization
- Annualized rate of visits to clinic, Emergency room (ER) and
hospitalizations, both overall and VOCrelated over the first year post
randomization
- Evolution of albuminuria and ACR over the first year post randomization
- PK parameters after the first and fifth dose (e.g., AUC, Cmax, Tmax,
half-life)
- PD parameter (P-selectin inhibition) after the first and fifth dose
- Annualized rate of VOCs leading to healthcare visit
- annualized rate of all VOCs leading to healthcare visit and treated at
home
- Annualized rate of VOCs managed at home
- Number, seriousness, severity, and causality assessments of treatment-emergent adverse events, including infections (serious, nonserious and opportunistic infections) and other safety data - as
considered appropriate
- Absolute change from baseline in hemoglobin
- Growth and sexual maturity assessment in adolescents (Tanner stage)
- Immunogenicity: measurement of anti-drug antibodies (ADA) to
crizanlizumab

E.5.2.1

Timepoint(s) of evaluation of this end point

1 year

- 1 year
- 1 year
- 5 years
- 5 years
- 5 years
- 5 years
- 5 years
- 5 years
- 5 years
- 5 years

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

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

healthcare resource utilization

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

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

Colombia

Egypt

Ghana

Oman

Panama

United Arab Emirates

Brazil

Canada

India

Jordan

Kenya

Lebanon

Saudi Arabia

South Africa

United Kingdom

United States

Belgium

Finland

France

Germany

Greece

Italy

Netherlands

Spain

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

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

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)

Yes

F.1.2.1

Number of subjects for this age range:

190

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

240

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)

Novartis will provide crizanlizumab to participants benefiting from continued treatment as per the Investigator's opinion after study completion until the earliest occurrence:
-Crizanlizumab is commercially available and reimbursed in the participant's country for this population, and participants are eligible to be prescribed the commercial drug
-Another clinical study becomes available that can continue to provide crizanlizumab in
this population
-Participant is no longer deriving benefit

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

2019-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-21

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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