Clinical Trials Register

Summary
EudraCT Number:	2014-003572-23
Sponsor's Protocol Code Number:	GCP#01.01.030
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-06-26
Trial results	View 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

France - ANSM

A.2

EudraCT number

2014-003572-23

A.3

Full title of the trial

Allogeneic Stem Cell Transplantation of CordIn™, Umbilical Cord Blood-Derived Ex Vivo Expanded Stem and Progenitor Cells, in Patients with Hemoglobinopathies

Greffe allogénique de cellules souches de CordIn™, cellules souches et progénitrices amplifiées ex vivo à partir de sang de cordon ombilical, chez des patients atteints d'hémoglobinopathies

A.3.1

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

Transplantation of CordIn, stem cells from donated umbilical cord blood that were grown in a laboratory to expand their number, in patients with a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule

Greffe de Cordin, cellules souches obtenues avec le don de sang de cordon ombilical et cultivées en laboratoire pour augmenter le nombre, chez des patients atteints d'un défaut génétique qui entraîne une structure anormale de l'une des chaînes de globine de la molécule d'hémoglobine

A.4.1

Sponsor's protocol code number

GCP#01.01.030

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	Gamida Cell Ltd
B.1.3.4	Country	Israel
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	Gamida Cell
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gamida Cell Ltd
B.5.2	Functional name of contact point	Clinical Trial department
B.5.3	Address:
B.5.3.1	Street Address	5, Nahum Hafzadi, Beit Ofer
B.5.3.2	Town/ city	Jerusalem
B.5.3.3	Post code	9548401
B.5.3.4	Country	Israel
B.5.4	Telephone number	97226595666

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	CordIn (CF cultured fraction and NF non-cultured fraction)
D.3.4	Pharmaceutical form	Suspension for injection
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	allogeneic, umbilical cord blood-derived, ex vivo expanded, hematopoietic CD133+ cells
D.3.9.3	Other descriptive name	ALLOGENEIC, UMBILICAL CORD BLOOD-DERIVED, EX VIVO EXPANDED, HEMATOPOIETIC CD133+ CELLS
D.3.9.4	EV Substance Code	SUB121492
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	1200000000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	allogeneic, umbilical cord blood-derived, non-expanded, hematopoietic CD133- cells
D.3.9.3	Other descriptive name	ALLOGENEIC, UMBILICAL CORD BLOOD-DERIVED, NON-EXPANDED, HEMATOPOIETIC CD133- CELLS
D.3.9.4	EV Substance Code	SUB130958
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	500000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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	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

Hemoglobinopathies

hémoglobinopathies

E.1.1.1

Medical condition in easily understood language

a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule

défaut génétique qui entraîne une structure anormale de l'une des chaînes de globine de la molécule d'hémoglobine

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10054658
E.1.2	Term	Thalassemia
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10040645
E.1.2	Term	Sickle cell disease NOS
E.1.2	System Organ Class	100000004850

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

Assess the acute toxicities associated with the infusion of CordIn, within 24 hours post-infusion
Assess the proportion of patients with donor-derived engraftment at 42 days following transplantation

Évaluer les toxicités aiguës associées à l'injection de CordIn™, dans les 24 heures suivant l'injection
Évaluer la proportion de patients obtenant une prise de greffe des cellules du donneur 42 jours post-greffe

E.2.2

Secondary objectives of the trial

Cumulative incidence of transplant-related mortality at day 100 after transplantation
Event-free survival at day 100 and 1 year after transplantation (patient’s death, autologous recovery, primary or secondary graft failure will be considered events for this endpoint)
Overall survival at 1 year after transplantation (patient’s death will be considered the relevant event)
RBC transfusion-free survival at 1 year in thalassemia patients
Proportion of treatment free HbS ≤ 30% at 1 year in SCD patients

Incidence cumulée de mortalité liée à la greffe au jour 100 post-greffe
Survie sans événement au jour 100 et un an après la greffe (le décès du patient, la récupération autologue, et l'échec de greffe primaire ou secondaire seront considérés comme des événements pour ce critère)
Survie globale un an après la greffe (le décès du patient sera considéré comme l'événement pertinent)
Survie sans transfusion de globules rouges à un an, chez les patients atteints de thalassémie
Proportion d'HbS sans traitement ≤30% à un an chez les patients atteints de drépanocytose

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Patients must be 2–25 years of age and at least 10kg
2.Patient is a candidate for allogeneic SCT for treatment of SCD or thalassemia:
a.Patient must have clinically severe SCD(eg. SS, SC or SBeta0 Thal) with at least one of the following clinical complications:
Recurrent painful events(at least 3 in the 2 years prior to enrollment) that cannot be explained by other causes. Pain may occur in typical sites associated with vaso-occlusive painful events and cannot be explained by causes other than sickle cell disease. Pain lasts at least 4 hours and requires parenteral narcotic treatment,equianalgesic dose of oral narcotics or parenteral nonsteroidal anti-inflamrnatory drugs. These painful events may be treated in any setting,but events managed at home will be considered only if there is documentation of the event in a clinical record that may be reviewed by an investigator. These events must occur despite adequate supportive care measures.
Acute chest syndrome with at least two episodes with the development of a new infiltrate on chest radiograph and/or having a perfusion defect demonstrable on a lung radioisotope scan within the past two years that required hospitalization, oxygen therapy, and RBC transfusion. These episodes must occur despite adequate supportive care measures.
Any combination of painful events and acute chest syndrome episodes that total three events within the two years before transplantation.
Any clinically significant neurologic event (stroke or hemorrhage) or any neurologic defect lasting more than 24 hours.
Patients on chronic PRBC transfusion therapy, defined as receiving 8 or more transfusions per year for > 1 year to prevent vaso-occlusive clinical complications (e.g. pain, stroke, and acute chest syndrome)
Abnormal cerebral MRI and abnormal cerebral MRA.
Abnormal Transcranial Doppler (TCD), as defined by a TCD velocity that exceeds 200 cm/sec by the non-imaging technique (or TCD measurement of >185 cm/sec by the imaging technique) measured at a minimum of two separate occasions one month or more apart
OR;
b.Patient must have thalassemia major requiring regular RBC transfusions
3.Patients must have a partially HLA-matched CBU. The unit must be HLA-matched at 4-6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci with the subject. For patients weighing ≥ 25 kg, the CBU must have a pre-cryopreserved, total CD34+ cell dose of ≥10x10^6 as well as a pre-cryopreserved total nucleated cell dose of ≥1.8x10^9. For patients weighing < 25 kg, the CBU must have a pre-cryopreserved, total CD34+ cell dose of ≥7x10^6 as well as a pre-cryopreserved total nucleated cell dose of ≥1.6x10^9.
4.The CBU will have undergone volume reduction (both plasma and red blood cell depletion) prior to cryopreservation.
5.Patients must have autologous stem cells harvested from bone marrow as a backup in case of graft failure.
6.Patients’ Performance score ≥70% by Lansky or Karnofsky performance status scale
7.Patient has sufficient physiologic reserves including:
Cardiac: Left ventricular ejection fraction (LVEF) > 50% by echocardiogram radionuclide scan or cardiac MRI; or LV shortening fraction > 26%.
Pulmonary: Pulse oximetry with a baseline O2 saturation of ≥ 85% is required for all patients, DLCO > 60% of predicted for age (corrected for hemoglobin) for patients in whom pulmonary function testing can be performed.
Renal: Serum creatinine ≤ 1.5 x upper limit of normal for age and GFR > 70 mL/min/1.73 m2.
Hepatic: Serum conjugated (direct) bilirubin < 2 x upper limit of normal for age as per local laboratory in the absence of gall bladder disease or prior cholecystectomy; Hepatic transaminases (ALT and AST) < 5 x upper limit of normal range
8.In SCD patients, HbS should be ≤ 45%, as measured in non-chronically RBC transfused patients, within 7 days prior to initiation of conditioning regimen. If the HbS level is >45% then the patient must receive RBC transfusions or erythrocyte exchange prior to conditioning regimen initiation.
9.Females of childbearing potential, defined as any female who has experienced menarche and is not postmenopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy), agree to use an appropriate method of contraception from at least 7 days prior to preparative therapy until completion of follow-up procedures. An appropriate method of contraception is defined as one that results in a low failure rate (i.e., less than 1 percent per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner.
10.Patient and/or legal guardian signs the written informed consent after being made aware of the nature of the patient’s disease and willingly consents to the treatment program after being informed of alternative treatments, potential risks, benefits, and discomforts

E.4

Principal exclusion criteria

1.Evidence of uncontrolled bacterial, viral or fungal infections or severe concomitant diseases, which in the judgment of the Principal Investigator, indicate that the patient could not tolerate transplantation
2.Evidence of HIV infection or HIV positive serology
3.Evidence of active Hepatitis B, Hepatitis C or EBV as determined by serology or PCR
4.Pregnancy, as indicated by a positive serum human chorionic gonadotrophin (HCG) test, or lactation
5.Patients with 10/10 or 9/10 HLA-matched related family donor or unrelated donor able to donate
6.Severe alloimmunization with inability to guarantee a supply of adequate PRBC donors
7.Evidence of anti-HLA antibodies to the selected CordIn™ CBU (MFI>1000)
8.Prior allogeneic hematopoietic stem cell transplant within last 12 months .
9.Allergy to bovine, Gentamicin, or to any product which may interfere with the treatment
10.Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance and/or psychiatric illness and/or social situations that would limit compliance with study requirements
11.Enrolled in another clinical trial or received an investigational treatment during the last 30 days, unless approved by Sponsor

E.5 End points

E.5.1

Primary end point(s)

1. acute toxicities associated with the infusion of CordIn™, within 24 hours post-infusion
2. proportion of patients with donor-derived engraftment at 42 days following transplantation

E.5.1.1

Timepoint(s) of evaluation of this end point

1. 24 hours
2. day 42

E.5.2

Secondary end point(s)

1. Cumulative incidence of transplant-related mortality at day 100 after transplantation
2. Event-free survival at day 100 and 1 year after transplantation (patient’s death, autologous recovery, primary or secondary graft failure will be considered events for this endpoint)
3. Overall survival at 1 year after transplantation (patient’s death will be considered the relevant event)
4. RBC transfusion-free survival at 1 year in thalassemia patients
5. Proportion of treatment free HbS ≤ 30% at 1 year in SCD patients

E.5.2.1

Timepoint(s) of evaluation of this end point

1. day 100
2. day 100 and 1 year
3. 1 year
4. 1 year
5. 1 year

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

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 I/II

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

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.8.5

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

Italy

United States

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

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

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)

when subject completes the study visits he will be offered to participate in the long term follow up study

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

2017-12-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-20

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