Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)
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|ClinicalTrials.gov Identifier: NCT01306019|
Recruitment Status : Recruiting
First Posted : March 1, 2011
Last Update Posted : March 29, 2018
|First Submitted Date ICMJE||February 26, 2011|
|First Posted Date ICMJE||March 1, 2011|
|Last Update Posted Date||March 29, 2018|
|Study Start Date ICMJE||February 26, 2011|
|Estimated Primary Completion Date||December 31, 2022 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||The primary objective is to assess the efficacy of immune reconstitution in XSCID patients transplanted with autologous CD34 plus cells that have been transduced with a self-inactivating lentiviral vector expressing a Gamma C gene. [ Time Frame: Primary endpoint evaluation at 2 years ]|
|Original Primary Outcome Measures ICMJE
||The primary objective is to assess the efficacy of immune reconstitution in XSCID patients transplanted with autologous CD34 plus cells that have been transduced with a self-inactivating lentiviral vector expressing a Gamma C gene.|
|Change History||Complete list of historical versions of study NCT01306019 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID)|
|Official Title ICMJE||Lentiviral Gene Transfer for Treatment of Children Older Than 2 Years of Age With X-Linked Severe Combined Immunodeficiency|
- To determine the safety and effectiveness of lentiviral gene transfer as a treatment for children and adolescents with X-linked severe combined immunodeficiency.
- Children and adolescents between 2 and 20 years of age who have XSCID related to a defect in the IL2RG gene and who are not currently under treatment with strong immune-modulating or chemotherapy drugs.
This is a non-randomized clinical trial of gene transfer using a self-inactivating, insulated, lentiviral gene transfer vector to treat 13 patients with X-linked severe combined immunodeficiency (XSCID, also called SCID-X1) who are between 2 and 40 years of age; who do not have a tissue matched sibling who can donate bone marrow for a transplant; who may have failed to obtain sufficient benefit from a previous half-tissue matched bone marrow transplant; and who have clinically significant impairment of immunity. A patient s own precursor cells (also called blood stem cells) that give rise in the marrow to blood and immune cells will have been or will be collected from the patient s blood or bone marrow. A patient will not proceed to gene transfer treatment in this protocol until there are at least 3 million blood stem cells per kilogram body weight collected from the patient. At the NIH the patient blood stem cells will be collected from either the blood or bone marrow under another protocol (NIH protocol 94-1-0073 or a successor approved protocol) that is specific for collection of such cells. In most cases the harvested blood stem cells are put into frozen storage before use in this protocol. When the patient enrolled in this protocol has the required number of blood stem cells harvested, then the patient s blood stem cells will be grown in tissue culture and exposed to the lentiviral gene transfer vector containing the corrective gene. These gene corrected blood stem cells will be administered by vein to the patient. To increase engraftment of the corrected blood stem cells, patients will receive on 2 days before the gene transfer treatment a chemotherapy drug called busulfan at a total dose of 6 mg/kilogram body weight (3 mg/kilogram body weight/daily times 2 days) that is a little more than one-third the dose used in many standard bone marrow transplants. Patients will also be given another drug called palifermin that helps prevent the main side effect from the busulfan that is a type of inflammation the mouth, stomach and bowels called mucositis. After this treatment, patients will be monitored to see if the treatment is safe and whether their immune system improves. Patients will be followed at frequent intervals for the first 2 years, and less frequently thereafter so that the effectiveness in restoration of immune function and the safety of the treatment can be evaluated.
XSCID is a genetic disease caused by defects in common gamma chain, a protein found at the surface of immune cells called lymphocytes and necessary to their growth and function. XSCID patients cannot make T-lymphocytes necessary to fight infections, and their B-cells fail to make essential antibodies. Without normal T- and B-lymphocyte function patients develop fatal infections in infancy unless they are rescued by a bone marrow transplant from a healthy donor. The best type of transplant is from a tissue matched healthy brother or sister, but most XSCID patients do not have a tissue matched sibling, and are treated with a transplant from a parent who is only half-matched by tissue typing. While a half-matched transplant from a parent can be life-saving for an infant with XSCID, a subset of patients fail to achieve sufficient long lasting restoration of immunity to prevent infections and other chronic problems.
Recent trials of gene transfer treatments using mouse retrovirus vectors for infants with XSCID have been performed and have demonstrated that this type of gene transfer can be an alternate approach for significantly restoring immunity to infants with XSCID. However, among the 18 infants with XSCID benefiting long term from the gene transfer treatment, 5 developed T-lymphocyte leukemia and 1 died of this leukemia. Furthermore, when older children with XSCID were treated with gene transfer, the restoration of immunity was very much less than seen in the infants. These observations of gene transfer treatments using mouse retrovirus vectors to treat infants and older patients with XSCID suggests that safer and more effective vectors were needed, and that there also may be a need to give chemotherapy conditioning to increase engraftment in the marrow of the gene corrected blood stem cells. Our data and other published studies suggest that lentivectors that are derived from the human immunodeficiency virus and have the properties of our highly modified vector called CL20-4i-EF1alpha- HgammaC-OPT have a reduced interaction with nearby genes and therefore less of a tendency to activate genes that may lead to cancer formation. Also, this type of lentivector may work better at getting into blood stem cells.
The study purpose is to evaluate safety and effectiveness of lentiviral gene transfer treatment at restoring immune function to 13 XSCID patients who are 2 to 40 years of age, and have significant impairment of immunity. Early evidence for effectiveness will be defined by appearance and expansion in the circulation of the patient s own gene corrected T-lymphocytes with a functional gammac gene and improved laboratory measures of immune function. The primary endpoint for efficacy will be at 2 years after treatment, and will include these laboratory parameters plus evidence for clinical benefit. Evidence for safety will focus on maintenance of a diversity of gene marked cells and no occurrence of abnormal pattern of production of blood cells or any leukemia or other cancer. The primary study endpoints for all laboratory and clinical measures of efficacy and safety will occur at 2 years after gene transfer treatment. However, data collection regarding efficacy will occur at frequent intervals during the 2 years leading up to the endpoint analysis, and long term safety and efficacy evaluation will continue at intervals during the long term follow-up required by regulation in gene transfer treatment studies.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Study Arms||Experimental: 1
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date||December 31, 2025|
|Estimated Primary Completion Date||December 31, 2022 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
IN ADDITION, patients must satisfy the following Laboratory Criteria AND Clinical Criteria
Laboratory Criteria: (greater than or equal to 1 must be present)
i. CD4+ lymphocytes: absolute number less than or equal to 50 percent of the lower limit of normal (LLN)
ii. CD4 plus CD45RA+ lymphocytes: absolute number less than or equal to 50 percent of the LLN OR T-cell receptor excision circles (TRECs)squared less than or equal to 5 percent of normal for age.
iii. Memory B Cells: absolute numberless than or equal to 50percent of LLN
iv. If serum IgM<normal for age
v. NK cells: absolute number less than or equal to 50 percent of LLN
vi. Lymphocyte proliferative response to each of 2 mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), is squared 25 percent with a normal control.
vii. Molecular spectratype analysis- absent or very oligoclonal (1-3 dominant peaks) in greater than or equal to 6 of the 24 V- Beta T-cell receptor families.
Clinical Criteria: (greater than or equal to 1 must be present):
i Infections (not including molluscum, warts or mucocutaneous candidiasis; see vii and viii below): greater than or equal to 3 significant new or chronic active infections during the 12 months preceding evaluation for enrollment.
Infections are defined as an objective sign of infection (fever greater than 38.3 degrees C [101 degrees F] or neutrophilia or pain/redness/swelling or radiologic/ultrasound imaging evidence or typical lesion or histology or new severe diarrhea or cough with sputum production). In addition to one or more of these signs/symptoms of possible infection, there also must be at least 1 of the following criteria as evidence of the attending physician s intent to treat a significant infection (a. and b.) or objective evidence for a specific pathogen causing the infection (c.)
-Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics greater than or equal to 14 days
-Hospitalization of any duration for infection
-Isolation of a bacteria, fungus, or virus from biopsy, skin lesion, blood, nasal washing, bronchoscopy, cerebrospinal fluid or stool likely to be an etiologic agent of infection
ii Chronic pulmonary disease as defined by:
-Bronchiectasis by x-ray computerized tomography
-Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is less than or equal to 60 percent of Predicted for Age
-Pulse oximetry less than or equal to 94 percent in room air (if patient is too young to comply with performance of PFTs).
iii Gastrointestinal enteropathy:
-Diarrhea-watery stools greater than or equal to 3 times per day (of at least 3 months duration that is not a result of infection as defined in criterion above)
-Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated)
-Other evidence of enteropathy or bacterial overgrowth syndrome: including malabsorption of fat soluble vitamin(s), abnormal D-xylose absorption, abnormal hydrogen breath test, evidence of protein losing enteropathy (for example increasingly high or frequent dosing of intravenous gamma globulin supplement required to maintain blood IgG level).
iv Poor nutrition: Requires G-tube or intravenous feeding supplement to maintain weight or nutrition.
v Auto- or allo-immunity: Examples must include objective physical findings that include, but are not limited to any one of alopecia, severe rashes, uveitis, joint pain with redness or swelling or limitation of movement that is not a result of infection, lupus-like lesions, and granulomas (Does not include auto- or allo-immune enteropathy which is criterion iii). Where possible and appropriate, diagnosis will be supported by histopathology or other diagnostic modality.
vi Failure to grow in height: less than or equal to 3 rd percentile for age
vii Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists of greater than or equal to 10 lesions or there are two or more lesions at each of two or more widely separated anatomic sites; or there are greater than or equal to 3 warts at different anatomic sites at the same time; or the patient has both molluscum and warts)
viii Mucocutaneous candidiasis (chronic oral thrush or candida esophagitis or candida intertriginous infection or candida nail infections; must be culture positive to satisfy this criterion)
|Ages||2 Years to 40 Years (Child, Adult)|
|Accepts Healthy Volunteers||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01306019|
|Other Study ID Numbers ICMJE||110007
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )|
|Study Sponsor ICMJE||National Institute of Allergy and Infectious Diseases (NIAID)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||February 15, 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP