Clinical Trials Register

Summary
EudraCT Number:	2012-000695-42
Sponsor's Protocol Code Number:	HGB-205
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:	2012-12-19
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

2012-000695-42

A.3

Full title of the trial

A Phase I/II Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the β-Hemoglobinopathies (Sickle Cell Anemia and β-Thalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with a Lentiviral beta-A-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)

A.3.1

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

Essai clinique de Phase I/II évaluant la sécurité et l’efficacité du produit de thérapie génique LentiGlobin BB305 Drug Product dans le traitement de la drépanocytose sévère et la béta-thalassémie majeure.

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

HGB-205

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	bluebird bio, Inc.
B.1.3.4	Country	United States
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	bluebird bio, Inc. (with its wholly owned subsidiary bluebird bio France)
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	NUVISAN ONCOLOGY SA
B.5.2	Functional name of contact point	Thierry Rousselot, Project Manager
B.5.3	Address:
B.5.3.1	Street Address	18-20 rue Pasteur
B.5.3.2	Town/ city	Le Kremlin Bicetre
B.5.3.3	Post code	94278
B.5.3.4	Country	France
B.5.4	Telephone number	+33(0)145 15 41 03
B.5.5	Fax number	+33(0)145 15 40 61
B.5.6	E-mail	thierry.rousselot@nuvisan.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	LentiGlobin BB305 Drug Product (autologous CD34 cells transduced w/ LentiGlobin BB305)
D.3.4	Pharmaceutical form	Suspension for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	EMA/CAT/988303/2011
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	Yes
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

Severe sickle cell anemia and transfusion-dependent beta-thalassemia major.
This study will enroll patients who are eligible for an allogeneic hematopoietic stem cell transplant (HSCT) but do not have a suitable, willing human leukocyte antigen (HLA)-identical sibling donor.

E.1.1.1

Medical condition in easily understood language

beta-thalassemia major and severe sickle cell anemia

beta-thalassemie majeure et drepanocytose severe

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10055579
E.1.2	Term	Sickle-cell beta thalassemia
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

Determine the safety, tolerability, and success of engraftment with autologous CD34+ hematopoietic stem cells transduced with LentiGlobin® BB305 lentiviral vector encoding the human beta-A-T87Q- globin gene and suspended in Albunorm™ (human serum albumin; HSA) 5% (i.e., LentiGlobin® BB305 Drug Product) after conditioning with Busulfex® (busulfan IV) in subjects with severe sickle cell anemia (SCA) or beta thalassemia major (beta ThalM).

E.2.2

Secondary objectives of the trial

I - Quantify gene transfer efficiency and expression:
•Evaluate expression of beta-A-T87Q-globin chain in peripheral blood burst forming units erythroid (BFU-Es), reticulocytes, and red blood cells (RBCs).
•Quantify the hematopoietic chimerism resulting from treatment with LentiGlobin® BB305 Drug Product (vector copy number [VCN]).

II - Measure the effects of transplantation with LentiGlobin® BB305 Drug Product on the expression of disease-specific biological parameters and clinical events, including the volume of blood transfusions for both severe sickle cell anemia and beta-thalassemia major and, for subjects with severe sickle cell anemia, the number of vaso-occlusive crises (VOC) and acute chest syndrome (ACS) events in each subject compared with the 2 year pre-treatment period.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All subjects must:
1.Be between 5 and 35 years of age, inclusive.
•Adult subjects (between 18 and 35 years of age, inclusive, at the time of consent) must be able to provide written consent.
•For pediatric subjects (between 5 and 17 years of age, inclusive, at the time of consent), a competent parent or legal guardian must be able to provide written informed consent. When possible, involvement of the child >7 years of age in the decision is highly recommended, and written assent will be obtained and should be clearly documented.
•Subjects aged 5 to 14 years require the approval from the Comité de Surveillance prior to enrollment.

2.Have severe SCA or transfusion dependent beta-ThalM, regardless of the genotype (e.g., β0, β+, βE/β0, βS/βS, βS/β0), with the diagnosis confirmed by Hb studies. Subjects with transfusion dependent beta-ThalM must be stable and maintained on an appropriate iron chelation regimen. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed RBCs.
3.Be candidates for HSCT.
4.Be willing and able, in the Investigator’s opinion, to comply with the study procedures outlined in the study protocol. If a pediatric subject, the subject’s parent/legal guardian also must be willing and able to comply with the study procedures outlined in the study protocol.
5.Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.

Subjects with severe SCA also must:
6.Have 1 or more of the following poor prognostic risk factors despite having had adequate therapy (at least 4 months duration) with hydroxyurea (unless they were unable to tolerate hydroxyurea therapy):
•Recurrent VOC and/or priapism (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program).
•Presence of cerebral vasculopathy requiring a long term transfusion program (at least 6 months).
•Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions).
•Stroke without any severe cognitive disability.
•Osteonecrosis of 2 or more joints.
•Red cell alloimmunization (>2 antibodies).
•Presence of sickle cell cardiomyopathy documented by Doppler echocardiography.
•Recurrent acute chest syndrome (at least 2 episodes in the preceding year) defined by the presence of a new pulmonary infiltrate involving at least 1 complete lung segment (but excluding atelectasis) associated with at least 1 new symptom: chest pain, fever (>38.5°C), tachypnea, wheezing or cough not explained by infection. Subjects with a chronic oxygen saturation <90% (excluding periods of SCA crisis) or carbon dioxide diffusing capacity (DLco) less than 60% in the absence of an infection should not be included in the study.

E.4

Principal exclusion criteria

All subjects must not meet any of the following:
1.Availability of a suitable, willing HLA identical sibling.
2.Positive for presence of human immunodeficiency virus type 1 or 2 (HIV 1 and HIV 2), human T lymphotrophic virus 1 (HTLV 1), vesicular stomatitis virus G (VSV G) antibody or VSV G ribonucleic acid (RNA).
3.Clinically significant, active bacterial, viral, or fungal infection.
4.Contraindication to anesthesia for bone marrow harvesting.
5.Any prior or current malignancy, myeloproliferative or immunodeficiency disorder.
6.A white blood cell (WBC) count <3×10^9/L and/or platelet count <120×10^9/L.
7.Receipt of an allogeneic transplant.
8.Receipt of erythropoietin within 3 months before HSCT harvest.
9.Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers).
10.Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study.
11.History of malaria relapses in the absence of recent infection.
12.History of complex allo immunization, which could cause difficulty administering transfusions.
13.Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects. Females of child bearing potential must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection throughout the 27 month study period.
14.History of major organ damage including:
•Liver disease, as evidenced by transaminase levels >3× upper limit of normal or the presence of histopathological evidence of liver cirrhosis on liver biopsy.
•Heart disease, with a left ventricular ejection fraction <25%.
•Kidney disease with a calculated creatinine clearance <30% normal value.
•Severe iron overload, which in the opinion of the physician is grounds for exclusion.
•A cardiac T2* <10 ms by MRI.
•Evidence of significant pulmonary hypertension.
15.Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician.
16.Participation in another clinical study with an investigational drug within 30 days of screening.
17.Subjects who have the desire to become a parent within the 27 month study period.
18.Prior receipt of gene therapy.
19.An assessment by the Investigator that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
Subjects with beta-ThalM also must not:
Be Pesaro Class III (poor compliance of iron chelation therapy, presence of hepatomegaly, and severe fibrosis) (Lucarelli et al., 2001).

E.5 End points

E.5.1

Primary end point(s)

SAFETY ENDPOINTS:
•Success and kinetics of HSC engraftment.
•Incidence of transplant related mortality through 100 days post treatment.
•Overall survival.
•Detection of vector derived RCL in any subject.
•Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia.
•Monitoring of laboratory parameters and frequency and severity of clinical adverse events (AEs), as assessed by the United States (US) National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03

EFFICACY ENDPOINTS:
The effects on the expression of disease specific biological parameters and clinical events will be measured, as follows:

For all subjects:
•RBC transfusion requirements (measured in milliliters [mL] per kilogram [kg]) per month and per year post transplant.
•Number of total in patient hospitalization days (post transplant discharge) at 6, 12, and 24 months.

For subjects with severe SCA only:
•Evaluation of cerebral vasculopathy at 6, 12, and 24 months.
•Number of VOC or acute chest syndrome events at 6, 12, and 24 months.
•Evaluation of changes in the nature or frequency of the subject specific main inclusion criteria.

PHARMACODYNAMIC ENDPOINTS:
To quantify both gene transfer efficiency and expression by measuring the following:
•Therapeutic globin expression, as measured by assessing the ratio of βA T87Q globin to αlpha globin in BFU-Es, reticulocytes, and red blood cells, as well as the amount of βA T87Q globin as a fraction of all β chains in RBCs. (In the absence of transfusions for a minimum of 3 months, βA T87Q globin will be assessed only in RBCs.)
•Average VCN in cell populations from peripheral blood and bone marrow containing the integrated LentiGlobin® BB305 lentiviral vector.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

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

The study will end when the last subject completes the Month 24 visit or discontinues from the study.

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

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

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.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)

After completion of HGB-205, subjects will be followed for long term safety and efficacy under a separate protocol for 13 years. Thus, subjects will be followed for a total of 15 years post-transplant.

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

2012-12-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-02-26

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