Severe Combined Immunodeficiency, X-LinkedPhase 1NCT03601286
Lentiviral Gene Therapy for X-linked Severe Combined Immunodeficiency
A Phase 1 study testing Lentiviral vector transduced CD34+ cells in people with Severe Combined Immunodeficiency, X-Linked, run by Great Ormond Street Hospital for Children NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. Read more about this study
- Who is it for?
- Ages 8 weeks to 5 years, men only
- Conditions the study is for
- Severe Combined Immunodeficiency, X-Linked
- What is being tested?
- Lentiviral vector transduced CD34+ cells
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 21 Dec 2018to Aug 2026
- Phase
- Phase 1
- 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 8 weeks to 5 years
- Men only
- No healthy volunteers
- Child
Who may be able to join
- Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA <10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG
- Lack of an HLA identical (A, B, C, DR, DQ) related donor
- Age <5 years
- Signed informed consent
- Documentation of willingness to follow up for 15 years post-infusion
- If the patient has previously undergone allogeneic transplant or gene therapy, insufficiency of graft-derived T cell engraftment must be documented.
- Age at least 8 weeks of age by the time of busulfan administration
Who cannot join
- Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below).
- Mechanical ventilation including continuous positive airway pressure
- Abnormal liver function defined by AST and ALT >10 times the upper range of normal OR Bilirubin >2 mg/dL
- Shortening fraction on echocardiogram <25% or ejection fraction <50%
- Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or dialysis dependence
- Uncontrolled seizure disorder
Show all 13Show fewer
- Encephalopathy
- Documented coexistence of any disorder known to affect DNA repair
- Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
- Patients with evidence of infection with HIV-1
- Previous allogeneic transplant with cytoreductive chemotherapy
- Major (life-threatening) congenital anomalies. Examples of "major (life-threatening) congenital anomalies" include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major central nervous system malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function.
- Other conditions which in the opinion of the P.I. or Co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient's inability to follow the protocol. These may include for example clinical ineligibility to receive anaesthesia, severe deterioration of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship.
Trial locations and contacts
1 site in 1 country.
Karen Oprych, Dr contact
United Kingdom1 site, 1 recruiting
- Recruiting
Great Ormond Street Hospital for Children NHS Foundation Trust
London, Greater London, WC1N 3JH
Claire Booth, MBBS, MRCPCH, MSc, PhD, c.booth@ucl.ac.uk
Karen Oprych, PhD, k.gladwin@ucl.ac.uk
About this study
Official title: Phase I/II Study of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan
Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. SCID arises from a variety of molecular defects which affect lymphocyte development and function. The most common form of SCID is an X-linked form (SCID-X1), which accounts for 30-50% of all cases. SCID-X1 is caused by defects in the common cytokine receptor gamma chain, which was originally identified as a component of the high affinity interleukin-2 receptor (IL2RG).
Allogeneic haematopoietic stem cell transplantation (HSCT), which replaces the patient's bone marrow with that of a healthy donor, is the only treatment that definitively restores the normal function of the bone marrow. HSCT is the first choice of treatment for patients with signs of bone marrow failure and a fully-matched related donor. However, patients without a fully-matched related donor have much worse overall outcomes from HSCT.
This study will investigate whether patients with SCID-X1 without a fully matched related donor may benefit from gene therapy. To do this the investigators propose to perform a phase I/II clinical trial to evaluate the safety and efficacy (effect) of gene therapy for SCID-X1 patients using a lentivirus delivery system containing the IL2RG gene. Up to 5 eligible SCID-X1 patients will undergo mobilisation and harvest of their haematopoietic stem precursor cells (HPSCs). In the laboratory the disabled lentivirus will be used to insert a normal human IL2RG gene into the patient's harvested HPSCs. Patients will receive chemotherapy conditioning prior to cell infusion, in order to enhance grafting. The genetically corrected stem cells will then be re-infused into the patient. Patients will be followed up for 2 years. This trial will determine whether gene therapy for SCID-X1 using a lentiviral vector is safe, feasible and effective
- Being tested
- Lentiviral vector transduced CD34+ cells
- Medical subject headings
- X-Linked Combined Immunodeficiency Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lentiviral vector transduced CD34+ cellsDrug
Also called G2SCID lentiviral vector transduced CD34+ cells
Gene therapy for X-linked Severe Combined Immunodeficiency will be performed by introduction a normal copy of the IL2RG gene into the blood forming stem cells (CD34+ cells) of the patient's bone marrow by using a type of gene delivery system (in this trial called a lentiviral vector). The gene corrected cells are then transplanted back into the patient.
| Study group | Role | What they receive |
|---|---|---|
| Lentiviral vector transduced CD34+ cells | Experimental | Single arm, non-randomised cohort of up to 5 patients with X-linked Severe Combined Immunodeficiency. CD34+ cells will be collected via bone marrow harvest or leukapheresis. The collected cells will then be purified, cultured and transduced with the G2SCID lentiviral vector. Transduced cells will be frozen. A minimum of 2.5 x 106/kg CD34+ cells after transduction with a minimum transduction efficiency of 0.7 copies/cell is required for infusion into the patient. The patient will receive non-myeloablative conditioning with intravenous busulfan the two or three days prior to cell infusion. The frozen cells will be thawed on the day of infusion and the cells administered according to hospital procedures. The patient will remain in hospital until sufficient cover of the patient's immune system Receives: Drug: Lentiviral vector transduced CD34+ cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
Measure event-free survival after 1 year after gene transfer
Event-free survival at 1 year post-infusion. Events will include death, infusion of unmanipulated back-up product for failure of haematopoietic recovery, and allogeneic transplant performed for poor immune reconstitution
Measured: 1 year
Measure T cell immune reconstitution: CD3+ T cell count
T cell reconstitution at 1 year post-infusion: CD3+ T cell count ≥300 cells/microliter in peripheral blood
Measured: 1 year
Measure T cell immune reconstitution; gene marking
T cell reconstitution at 1 year post-infusion: Gene marking ≥0.1 copies/cell in sorted CD3+ T cells
Measured: 1 year
Secondary outcomes (16)
Measure overall survival
Measure overall survival at 2 years post-infusion
Measured: 2 years
Measure event-free survival
Measure event-free survival at 2 years post-infusion
Measured: 2 years
Incidence of adverse events related to gene therapy
Incidence of adverse events related to gene therapy
Measured: up to 2 years post-infusion of gene therapy
Enumeration of absolute lymphocyte count determined by routine complete reconstitution
Enumeration of absolute lymphocyte count determined by routine complete blood counts (CBC)
Measured: up to 2 years post-infusion of gene therapy
Haematopoietic recovery after receipt of busulfan
Haematopoietic recovery is defined as absolute neutrophil count above 0.5 x10^9 /l for three consecutive days, achieved within 6 weeks following infusion.
Measured: up to 6 weeks post-infusion of gene therapy
Measure absolute numbers of T, B and NK lymphocytes
Absolute numbers of T, B and NK lymphocytes
Measured: up to 2 years post-infusion of gene therapy
Calculate percentage of naïve and memory T cell subsets
Percentage of naïve and memory T cell subsets
Measured: up to 2 years post-infusion of gene therapy
Measure laboratory results which correlates with efficacious immune reconstitution
Percentage of naïve and memory B cell subsets
Measured: up to 2 years post-infusion of gene therapy
Determine Freedom from immunoglobulin substitution for at least 9 months
Freedom from immunoglobulin substitution for at least 9 months
Measured: 2 years post-infusion of gene therapy
Measure serum immunoglobulin levels reconstitution
Serum immunoglobulin levels
Measured: up to 2 years post-infusion of gene therapy
Measure proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation reconstitution
Proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation
Measured: up to 2 years post-infusion of gene therapy
Measure antigen specific antibody titres to tetanus toxoid reconstitution
Measure antigen specific antibody titres to tetanus toxoid
Measured: up to 2 years post-infusion of gene therapy
Measure T cell receptor excision circles (TREC)
Measure T cell receptor excision circles (TREC)
Measured: up to 2 years post-infusion of gene therapy
Measure T cell receptor Vb family usage
Measure T cell receptor Vb family usage
Measured: up to 2 years post-infusion of gene therapy
To assess the efficacy of stem cell transduction/engraftment by measuring the frequency of gene marking in peripheral blood cells
Gene marking in specific lineages of peripheral blood cells. Genomic DNA isolated from each population will be assayed for VCN by quantitative PCR (qPCR). The results will be aggregated to determine the effectiveness of gene marking in the peripheral blood cells.
Measured: up to 2 years post-infusion of gene therapy
Measure clonal diversity of vector integrants
Clonal diversity will be quantitated and used to estimate the number of transduced haematopoietic stem cells that have engrafted in the subjects. Number of sequence reads and unique integration sites will be assessed to quantify population clone diversity, distribution of integration sites and relative abundance.
Measured: up to 2 years post-infusion of gene therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2018
- Study start21 Dec 2018
- Primary completionAug 2026 (estimated)
- Study completionAug 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Severe Combined Immunodeficiency, X-LinkedStudies 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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Great Ormond Street Hospital for Children NHS Foundation Trust
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Claire Booth, Dr, Principal investigator, UCL Great Ormond Street Institute of Child HealthAdrian Thrasher, Prof, Principal investigator, UCL Great Ormond Street Institute of Child Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03601286
- Sponsor's protocol ID
- 16IC17
- Status last verified
- Oct 2023
- First submitted
- 22 Feb 2018
- Last updated
- 12 Oct 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan
- ClinicalTrials.gov ID
- NCT03601286
- Acronym / sponsor ID
- 16IC17
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 5 participants (estimated)
- Lead sponsor
- Great Ormond Street Hospital for Children NHS Foundation TrustUniversity, hospital or other
- Study start
- 21 Dec 2018 (actual)
- Primary completion
- Aug 2026 (estimated)
- Study completion
- Aug 2026 (estimated)
- First posted
- 26 Jul 2018 (actual)
- 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.
Severe combined immunodeficiency disorder (SCID) is a heterogeneous group of inherited disorders characterized by a profound reduction or absence of T lymphocyte function, resulting in lack of both cellular and humoral immunity. SCID arises from a variety of molecular defects which affect lymphocyte development and function. The most common form of SCID is an X-linked form (SCID-X1), which accounts for 30-50% of all cases. SCID-X1 is caused by defects in the common cytokine receptor gamma chain, which was originally identified as a component of the high affinity interleukin-2 receptor (IL2RG).
Allogeneic haematopoietic stem cell transplantation (HSCT), which replaces the patient's bone marrow with that of a healthy donor, is the only treatment that definitively restores the normal function of the bone marrow. HSCT is the first choice of treatment for patients with signs of bone marrow failure and a fully-matched related donor. However, patients without a fully-matched related donor have much worse overall outcomes from HSCT.
This study will investigate whether patients with SCID-X1 without a fully matched related donor may benefit from gene therapy. To do this the investigators propose to perform a phase I/II clinical trial to evaluate the safety and efficacy (effect) of gene therapy for SCID-X1 patients using a lentivirus delivery system containing the IL2RG gene. Up to 5 eligible SCID-X1 patients will undergo mobilisation and harvest of their haematopoietic stem precursor cells (HPSCs). In the laboratory the disabled lentivirus will be used to insert a normal human IL2RG gene into the patient's harvested HPSCs. Patients will receive chemotherapy conditioning prior to cell infusion, in order to enhance grafting. The genetically corrected stem cells will then be re-infused into the patient. Patients will be followed up for 2 years. This trial will determine whether gene therapy for SCID-X1 using a lentiviral vector is safe, feasible and effective
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Lentiviral vector transduced CD34+ cells | Experimental | Drug: Lentiviral vector transduced CD34+ cellsSingle arm, non-randomised cohort of up to 5 patients with X-linked Severe Combined Immunodeficiency. CD34+ cells will be collected via bone marrow harvest or leukapheresis. The collected cells will then be purified, cultured and transduced with the G2SCID lentiviral vector. Transduced cells will be frozen. A minimum of 2.5 x 106/kg CD34+ cells after transduction with a minimum transduction efficiency of 0.7 copies/cell is required for infusion into the patient. The patient will receive non-myeloablative conditioning with intravenous busulfan the two or three days prior to cell infusion. The frozen cells will be thawed on the day of infusion and the cells administered according to hospital procedures. The patient will remain in hospital until sufficient cover of the patient's immune system |
Who may qualify
- Ages
- 8 weeks to 5 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (7 listed)
- Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA <10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG
- Lack of an HLA identical (A, B, C, DR, DQ) related donor
- Age <5 years
- Signed informed consent
- Documentation of willingness to follow up for 15 years post-infusion
Key exclusion criteria (13 listed)
- Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below).
- Uncontrolled seizure disorder
- Encephalopathy
- Documented coexistence of any disorder known to affect DNA repair
- Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
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 |
|---|---|---|
| Lentiviral vector transduced CD34+ cellsAlso: G2SCID lentiviral vector transduced CD34+ cellsGene therapy for X-linked Severe Combined Immunodeficiency will be performed by introduction a normal copy of the IL2RG gene into the blood forming stem cells (CD34+ cells) of the patient's bone marrow by using a type of gene delivery system (in this trial called a lentiviral vector). The gene corrected cells are then transplanted back into the patient. | Drug | Lentiviral vector transduced CD34+ cells |
Primary outcome
Measure event-free survival after 1 year after gene transfer
Time frame: 1 year
Event-free survival at 1 year post-infusion. Events will include death, infusion of unmanipulated back-up product for failure of haematopoietic recovery, and allogeneic transplant performed for poor immune reconstitution
Measure T cell immune reconstitution: CD3+ T cell count
Time frame: 1 year
T cell reconstitution at 1 year post-infusion: CD3+ T cell count ≥300 cells/microliter in peripheral blood
Measure T cell immune reconstitution; gene marking
Time frame: 1 year
T cell reconstitution at 1 year post-infusion: Gene marking ≥0.1 copies/cell in sorted CD3+ T cells
16 secondary outcomes
Measure overall survival
Time frame: 2 years
Measure event-free survival
Time frame: 2 years
Incidence of adverse events related to gene therapy
Time frame: up to 2 years post-infusion of gene therapy
Enumeration of absolute lymphocyte count determined by routine complete reconstitution
Time frame: up to 2 years post-infusion of gene therapy
Haematopoietic recovery after receipt of busulfan
Time frame: up to 6 weeks post-infusion of gene therapy
Measure absolute numbers of T, B and NK lymphocytes
Time frame: up to 2 years post-infusion of gene therapy
Calculate percentage of naïve and memory T cell subsets
Time frame: up to 2 years post-infusion of gene therapy
Measure laboratory results which correlates with efficacious immune reconstitution
Time frame: up to 2 years post-infusion of gene therapy
Determine Freedom from immunoglobulin substitution for at least 9 months
Time frame: 2 years post-infusion of gene therapy
Measure serum immunoglobulin levels reconstitution
Time frame: up to 2 years post-infusion of gene therapy
Measure proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation reconstitution
Time frame: up to 2 years post-infusion of gene therapy
Measure antigen specific antibody titres to tetanus toxoid reconstitution
Time frame: up to 2 years post-infusion of gene therapy
Measure T cell receptor excision circles (TREC)
Time frame: up to 2 years post-infusion of gene therapy
Measure T cell receptor Vb family usage
Time frame: up to 2 years post-infusion of gene therapy
To assess the efficacy of stem cell transduction/engraftment by measuring the frequency of gene marking in peripheral blood cells
Time frame: up to 2 years post-infusion of gene therapy
Measure clonal diversity of vector integrants
Time frame: up to 2 years post-infusion of gene therapy
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Oct 2023.
- Individual participant dataSharing planned: No
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Base-Edited Hematopoietic Stem/Progenitor Cell X-Linked Severe Combined Immunodeficiency Gene Therapy
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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.
Karen Oprych, Dr contact
Claire Booth, Dr principal investigator
UCL Great Ormond Street Institute of Child Health
Adrian Thrasher, Prof principal investigator
UCL Great Ormond Street Institute of Child Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Lentiviral vector transduced CD34+ cells in people with Severe Combined Immunodeficiency, X-Linked, run by Great Ormond Street Hospital for Children NHS Foundation Trust at 1 site in United Kingdom.
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 7 inclusion and 13 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 12 Oct 2023. 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 United Kingdom. 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 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.
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?
Contact Claire Booth, Dr (0207 905 2198, c.booth@ucl.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Measure event-free survival after 1 year after gene transfer (time frame: 1 year). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 12 Oct 2023; AzTrials last refreshed its copy on 7 Nov 2026.