Beta-ThalassemiaPhase 1/2TIGET-BTHALNCT02453477

Gene Therapy for Transfusion Dependent Beta-thalassemia

A Phase 1/2 study testing Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene in people with Beta-Thalassemia, run by IRCCS San Raffaele at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record

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Trial summary

This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene for the treatment of patients affected by transfusion dependent beta-thalassemia Read more about this study

Who is it for?: Ages 3 to 64 years
Conditions the study is for: Beta-Thalassemia
What is being tested?: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 10 participants
Where: 1 siteItaly
Study dates: May 2015to Aug 2019
Phase: Phase 1/2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 3 to 64 years
All sexes
No healthy volunteers
Child, Adult

Who may be able to join

Written informed consent
Transfusion-dependent beta-thalassemia (any genotype). Transfusion dependence is defined as receiving ≥ 8 transfusions of blood per year over a minimum of 2 years.
Karnofsky Index or Lansky > 80%
Age ≥ 3 years and < 65 years
Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
Left ventricular ejection fraction (LVEF) greater than 45% by echo and normal ECG or presence of abnormalities not significant for cardiac disease. Absence of severe pulmonary hypertension

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Diffusing capacity of the lung for carbon monoxide (DLCO) > 50% and forced expiratory volume in 1 sec (FEV1) and forced expiratory vital capacity (FVC) > 60% predicted (if non cooperative: pulse oximetry > 95 % in room air)
Serum creatinine < 1.5 upper limit of normal
Absent-mild-moderate liver iron overload on T2*MRI (less than 12 months before enrolment)
Absent-mild-moderate cardiac iron overload T2*MRI (less than 12 months before enrolment)
Absence of severe liver fibrosis or cirrhosis on fibroscan or liver biopsy (less than 12 months before enrolment)
Low risk thrombophilic screen and negative history of significant previous thrombotic events
For all patients in reproductive age, agreement to use highly effective and adequate method of contraception while receiving treatment phase and for at least 12 months following drugs administration (including both females of child bearing potential and males with partners of child bearing potential)
Good adherence to transfusion and chelation programme as indirect evidence of good adherence to treatment and follow-up evaluations for current trial
Availability of an adequate and well documented transfusion history (at least previous 6 months) or availability to follow a regular transfusion regimen according to guidelines and provide a detailed transfusion record of the 6 months prior to intervention phase

Who cannot join

Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
Severe, active viral, bacterial, or fungal infection at eligibility evaluation
Malignant neoplasia (except local skin cancer or cervical intraepithelial neoplasia) or exceptional family history of familial cancer syndromes
Myelodysplasia, cytogenetic alterations associated with neoplasia, or other serious haematological disorder than thalassemia
History of uncontrolled seizures
Other clinical conditions judged non compatible with the procedure and/or the treatment

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Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA (or negative HCV RNA but on antiviral treatment) and/or Treponema Pallidum or Mycoplasma active infection
Active alcohol or substance abuse within 6 months of the study
Pregnancy or lactation
Previous allogeneic bone marrow transplantation or gene therapy
For paediatric patients only: availability of an HLA-matched donor (sibling or of a suitable 10/10 matched unrelated donor).

Trial locations and contacts

1 site in 1 country.

Italy1 site

Ospedale San Raffaele
Milan, 20132

Other trials in Italy

About this study

Official title: A Phase I/II Study Evaluating Safety and Efficacy of Autologous Hematopoietic Stem Cells Genetically Modified With GLOBE Lentiviral Vector Encoding for the Human Beta-globin Gene for the Treatment of Patients Affected by Transfusion Dependent Beta-thalassemia

Read the detailed description

Both adults and pediatric patients will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow for patients < 8 years in case mobilization will not be feasible) and transduced with GLOBE lentiviral vector encoding for the human beta-globin gene.

This study will enroll 10 patients allocated in 3 groups, according to age and conditioning regimen:

3 adults (≥18 years) conditioned with treosulfan and thiotepa
3 elderly children (8-17 years) conditioned with treosulfan and thiotepa
4 younger children (3-7 years) conditioned with treosulfan and thiotepa Enrolment will start in adult patients. Pediatric patients will be included once evidence of preliminary safety and biological efficacy is shown in at least 2 adults.

Patients are included regardless of the beta globin gene mutation, provided an adequate cardiac, renal, hepatic and pulmonary function is demonstrated. Patients with severe iron overload are excluded as well as patients with active viral infections. Pediatric patients can be enrolled only in absence of a human leukocyte antigen (HLA)-identical sibling or a suitable 10/10 matched unrelated donor.

The treated patients will be followed for 2 years. After completion of the 2 years follow up, patients will be enrolled in a long term follow up study and followed up for at least other additional 6 years.

Conditions: Beta-Thalassemia
Being tested: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Keywords: Beta thalassemia, Gene therapy, Lentiviral vector
Medical subject headings: beta-Thalassemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin geneGenetic
Autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10^6/Kg and a maximum dose of 20 x 10^6/Kg, depending on the yield of cells. The product will be injected intraosseously.

Study groups in NCT02453477
Study group	Role	What they receive
Adults	Experimental	≥18 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously. Receives: Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Elderly children	Experimental	8-17 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously. Receives: Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Younger children	Experimental	3-7 years (4 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously. Receives: Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene

What is being measured

The primary outcome is the main question the study is designed to answer.

Overall survival
Number of patients alive all over the trial
Measured: 2 years
Achievement of hematological engraftment
Haematological engraftment is defined as first day of neutrophil count >500/mm3 and platelets >20,000/mm3 on 3 consecutive blood counts.
Measured: within day +60 after gene therapy
Safety of the administration of autologous haematopoietic stem cells transduced with LV-GLOBE
- short-term tolerability: the percentage of patients not experiencing short-term (0-24 hours from injection) adverse events (of any grade) and systemic reactions.
- absence of Replication Competent Lentivirus (RCL): the percentage of subjects without RCL in the 24 months from injection.
- absence of abnormal clonal proliferation: the percentage of subjects without abnormal clonal proliferation in the 24 months from injection.
Measured: 0-24 months after gene therapy
Short-term safety and tolerability of the different conditioning regimens
The percentage of patients with the following clinical events from day -5 to +100 days from injection: NCI (National Cancer Institute Common Terminology Criteria grading) ≥2 and metabolic/laboratory NCI ≥3.
Measured: from day -5 (first day of conditioning treatment) to day 100 after gene therapy
Overall safety and tolerability measured by AE recording
The number of AEs (adverse events) and SAEs (serious adverse events) and the percentage of subjects experiencing AEs and SAEs in the 24 months post injection will be summarized by severity and within body system involved.
Measured: 0-24 months after gene therapy
Polyclonal engraftment
The percentage of subjects with polyclonality of haematopoiesis will be estimated at 6, 12, 18 and 24 months from injection. Polyclonality of haematopoiesis will be defined as > 1000 unique integration sites retrieved from peripheral blood and/or bone marrow cells.
Measured: From 6 months to 2 years after gene therapy
Reduction in transfusion frequency up to transfusion independence
Transfusions will be recorded as mLs of blood/kg/months
Measured: from -7 months before gene therapy to 2 years after gene therapy

Secondary outcomes (5)

Transfusion independence
Transfusion independence is defined as ≤ 1 transfusion in the previous 6 months
Measured: 9 months, 1, 1.5 and 2 years after gene therapy
Adequate haemoglobin level
Haemoglobin level will be assessed by full blood counts in patients achieving transfusion independence. Adequate haemoglobin is defined as haemoglobin >9 g/dl in adults and >10 g/dl in children.
Measured: 0-24 months after gene therapy
Adequate engraftment of genetically corrected cells
Engraftment will be assessed by vector-specific quantitative Polymerase Chain reaction (PCR) on bone marrow. Adequate engraftment is defined as ≥ 0.15 VCN/genome. (VCN = Vector Copy Number)
Measured: 6, 12, and 24 months after gene therapy
Transgene expression
Transgene expression will be evaluated by globin chains and/or hemoglobin synthesis on peripheral blood and/or bone marrow samples by HPLC and/or electrophoresis analysis
Measured: 6, 12, and 24 months after gene therapy
Improvement of health-related quality of life
Health-related quality of life will be assessed by the use of standardized questionnaires
Measured: 12 and 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

May 2015Aug 2019

First posted25 May 2015 (estimated)
Study startMay 2015
Primary completionAug 2019 (estimated)
Study completionAug 2019 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (8)Papers the sponsor has linked to this study.
Other trials for Beta-ThalassemiaStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 10 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02453477
Sponsor's protocol ID: 2014-004860-39 (EudraCT)
Other IDs: 2014
Acronym: TIGET-BTHAL
Status last verified: Jun 2019
First submitted: 15 May 2015
Last updated: 28 Jun 2019
Results posted: No
Data monitoring committee: Yes

Publications

Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013 Aug 23;341(6148):1233151. doi: 10.1126/science.1233151. Epub 2013 Jul 11.
PubMed 23845947
Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007 Aug;117(8):2233-40. doi: 10.1172/JCI31666.
PubMed 17671653
Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58. doi: 10.1056/NEJMoa0805817.
PubMed 19179314
Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.
PubMed 23845948
Frittoli MC, Biral E, Cappelli B, Zambelli M, Roncarolo MG, Ferrari G, Ciceri F, Marktel S. Bone marrow as a source of hematopoietic stem cells for human gene therapy of beta-thalassemia. Hum Gene Ther. 2011 Apr;22(4):507-13. doi: 10.1089/hum.2010.045. Epub 2011 Mar 4.
PubMed 20979441
Miccio A, Cesari R, Lotti F, Rossi C, Sanvito F, Ponzoni M, Routledge SJ, Chow CM, Antoniou MN, Ferrari G. In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10547-52. doi: 10.1073/pnas.0711666105. Epub 2008 Jul 23.
PubMed 18650378
Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi Sergi L, Benedicenti F, Ambrosi A, Di Serio C, Doglioni C, von Kalle C, Naldini L. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol. 2006 Jun;24(6):687-96. doi: 10.1038/nbt1216. Epub 2006 May 28.
PubMed 16732270
Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F, Mastropietro F, Amato A, Tonon G, Refaldi C, Cappellini MD, Andreani M, Lucarelli G, Roncarolo MG, Marktel S, Ferrari G. Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO Mol Med. 2010 Aug;2(8):315-28. doi: 10.1002/emmm.201000083.
PubMed 20665635

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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ALS20-101 Lentiviral Gene Therapy for Beta Thalassemia
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A Study to Investigate the Efficacy, Pharmacokinetics, and Safety of Mitapivat in Pediatric Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)
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Active, not recruitingPhase 3
A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)
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All Beta-Thalassemia trials

Study at a glance

From the registry record, last updated by the sponsor on 28 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase I/II Study Evaluating Safety and Efficacy of Autologous Hematopoietic Stem Cells Genetically Modified With GLOBE Lentiviral Vector Encoding for the Human Beta-globin Gene for the Treatment of Patients Affected by Transfusion Dependent Beta-thalassemia
ClinicalTrials.gov ID: NCT02453477
Acronym / sponsor ID: TIGET-BTHAL / 2014-004860-39 (EudraCT)
Conditions: Beta-Thalassemia
Keywords: Beta thalassemia, Gene therapy, Lentiviral vector
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Unknown status
Enrolment: 10 participants (actual)
Lead sponsor: IRCCS San RaffaeleUniversity, hospital or other
Collaborators: Fondazione Telethon, Orchard Therapeutics
Study start: May 2015
Primary completion: Aug 2019 (estimated)
Study completion: Aug 2019 (estimated)
First posted: 25 May 2015 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

This study will enroll 10 patients allocated in 3 groups, according to age and conditioning regimen:

3 adults (≥18 years) conditioned with treosulfan and thiotepa
3 elderly children (8-17 years) conditioned with treosulfan and thiotepa
4 younger children (3-7 years) conditioned with treosulfan and thiotepa Enrolment will start in adult patients. Pediatric patients will be included once evidence of preliminary safety and biological efficacy is shown in at least 2 adults.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Adults	Experimental	Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene≥18 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously.
Elderly children	Experimental	Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene8-17 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously.
Younger children	Experimental	Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene3-7 years (4 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously.

Who may qualify

Ages: 3 to 64 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult

Key inclusion criteria (15 listed)

Written informed consent
Transfusion-dependent beta-thalassemia (any genotype). Transfusion dependence is defined as receiving ≥ 8 transfusions of blood per year over a minimum of 2 years.
Karnofsky Index or Lansky > 80%
Age ≥ 3 years and < 65 years
Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:

Key exclusion criteria (11 listed)

Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
Severe, active viral, bacterial, or fungal infection at eligibility evaluation
Malignant neoplasia (except local skin cancer or cervical intraepithelial neoplasia) or exceptional family history of familial cancer syndromes
Myelodysplasia, cytogenetic alterations associated with neoplasia, or other serious haematological disorder than thalassemia
History of uncontrolled seizures

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin geneAutologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10^6/Kg and a maximum dose of 20 x 10^6/Kg, depending on the yield of cells. The product will be injected intraosseously.	Genetic	Adults, Elderly children, Younger children

Primary outcome

Overall survival
Time frame: 2 years
Number of patients alive all over the trial
Achievement of hematological engraftment
Time frame: within day +60 after gene therapy
Haematological engraftment is defined as first day of neutrophil count >500/mm3 and platelets >20,000/mm3 on 3 consecutive blood counts.
Safety of the administration of autologous haematopoietic stem cells transduced with LV-GLOBE
Time frame: 0-24 months after gene therapy
* short-term tolerability: the percentage of patients not experiencing short-term (0-24 hours from injection) adverse events (of any grade) and systemic reactions. * absence of Replication Competent Lentivirus (RCL): the percentage of subjects without RCL in the 24 months from injection. * absence of abnormal clonal proliferation: the percentage of subjects without abnormal clonal proliferation in the 24 months from injection.
Short-term safety and tolerability of the different conditioning regimens
Time frame: from day -5 (first day of conditioning treatment) to day 100 after gene therapy
The percentage of patients with the following clinical events from day -5 to +100 days from injection: NCI (National Cancer Institute Common Terminology Criteria grading) ≥2 and metabolic/laboratory NCI ≥3.
Overall safety and tolerability measured by AE recording
Time frame: 0-24 months after gene therapy
The number of AEs (adverse events) and SAEs (serious adverse events) and the percentage of subjects experiencing AEs and SAEs in the 24 months post injection will be summarized by severity and within body system involved.
Polyclonal engraftment
Time frame: From 6 months to 2 years after gene therapy
The percentage of subjects with polyclonality of haematopoiesis will be estimated at 6, 12, 18 and 24 months from injection. Polyclonality of haematopoiesis will be defined as > 1000 unique integration sites retrieved from peripheral blood and/or bone marrow cells.
Reduction in transfusion frequency up to transfusion independence
Time frame: from -7 months before gene therapy to 2 years after gene therapy
Transfusions will be recorded as mLs of blood/kg/months

5 secondary outcomes

Transfusion independence
Time frame: 9 months, 1, 1.5 and 2 years after gene therapy
Adequate haemoglobin level
Time frame: 0-24 months after gene therapy
Adequate engraftment of genetically corrected cells
Time frame: 6, 12, and 24 months after gene therapy
Transgene expression
Time frame: 6, 12, and 24 months after gene therapy
Improvement of health-related quality of life
Time frame: 12 and 24 months

Results and safety

Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 28 Jun 2019.
Background: PubMed 23845947Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013 Aug 23;341(6148):1233151. doi: 10.1126/science.1233151. Epub 2013 Jul 11.
Background: PubMed 17671653Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007 Aug;117(8):2233-40. doi: 10.1172/JCI31666.
Background: PubMed 19179314Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58. doi: 10.1056/NEJMoa0805817.
Background: PubMed 23845948Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.
Background: PubMed 20979441Frittoli MC, Biral E, Cappelli B, Zambelli M, Roncarolo MG, Ferrari G, Ciceri F, Marktel S. Bone marrow as a source of hematopoietic stem cells for human gene therapy of beta-thalassemia. Hum Gene Ther. 2011 Apr;22(4):507-13. doi: 10.1089/hum.2010.045. Epub 2011 Mar 4.
Background: PubMed 18650378Miccio A, Cesari R, Lotti F, Rossi C, Sanvito F, Ponzoni M, Routledge SJ, Chow CM, Antoniou MN, Ferrari G. In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10547-52. doi: 10.1073/pnas.0711666105. Epub 2008 Jul 23.
Background: PubMed 16732270Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi Sergi L, Benedicenti F, Ambrosi A, Di Serio C, Doglioni C, von Kalle C, Naldini L. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol. 2006 Jun;24(6):687-96. doi: 10.1038/nbt1216. Epub 2006 May 28.
Background: PubMed 20665635Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F, Mastropietro F, Amato A, Tonon G, Refaldi C, Cappellini MD, Andreani M, Lucarelli G, Roncarolo MG, Marktel S, Ferrari G. Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO Mol Med. 2010 Aug;2(8):315-28. doi: 10.1002/emmm.201000083.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Alessandro Aiuti, MD, PhD principal investigator

Ospedale San Raffaele

Fabio Ciceri, MD study chair

Ospedale San Raffaele

Sarah Marktel, MD study chair

Ospedale San Raffaele

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 28 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall survival (time frame: 2 years). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02453477, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jun 2019.