Donor Stem Cell Transplantation for Congenital Immunodeficiencies
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|ClinicalTrials.gov Identifier: NCT00426517|
Recruitment Status : Completed
First Posted : January 24, 2007
Last Update Posted : November 5, 2019
|First Submitted Date ICMJE||January 23, 2007|
|First Posted Date ICMJE||January 24, 2007|
|Last Update Posted Date||November 5, 2019|
|Study Start Date ICMJE||January 19, 2007|
|Actual Primary Completion Date||November 1, 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||The primary objective for this study is to evaluate the use of immunosuppressive drugs such as Campath -1H or h-ATG, fludarabine, and sirolimus in conjunction with a novel busulfan-based conditioning regimen with or without the addition of radia... [ Time Frame: End of Study ]|
|Original Primary Outcome Measures ICMJE
||Attain phenotypic correction of the disease|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
||Obtain engraftment without development of graft vs host disease, establish stable mixed chimerism, improve radity of immune reconstitution, determine days to neutrophil recovery, measure incidence of CMV reactivation, measure transfusion requirements|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Donor Stem Cell Transplantation for Congenital Immunodeficiencies|
|Official Title ICMJE||Allogeneic and Matched Unrelated Donor Stem Cell Transplantation for Congenital Immunodeficiencies or Patients With Autoinflammatory/Immunodysregulatory Conditions: Busulfan-Based Conditioning With Campath- 1H or h-ATG, Radiation, and Sirolimus|
This study uses transplantation to treat patients with problems in their immune system. The immune system cells come from the bone marrow where they grow from special cells called stem cells. Giving patients stem cells from someone else may help to cure many patients with certain immune diseases. This is called 'bone marrow transplantation'. This procedure can have side effects that are life-threatening. To try to make transplantation safer we are using lower doses of the medications used in preparing the patient for the transplant.
'Conditioning' treatments are given to patients to create space in their bone marrow. This lets the cells of the donor go into the bone marrow and produce normal immune cells. This study will use lower doses of a drug called busulfan and lower doses of radiation than what are currently being used in other kinds of bone marrow transplantation for other diseases.
Another problem that can occur with bone marrow transplantation is 'graft-versus-host disease'. This happens when the cells of the donor attacks different parts of the patient s body. This study will use a medicine called sirolimus instead of the usual medicine, cyclosporine, to prevent graft-versus-host disease.
To go onto this study, you must have:
Two groups of patients are included in this study:
Patients will have the following procedures:
This is an open-label pilot study of HLA-matched allogneic and matched unrelated donor (MUD) hematopoietic stem cell (HSC) transplant (also referred to as peripheral blood stem cell (PBSC) or bone marrow transplant (BMT)) for patients with X-linked severe combined immune deficiency (XSCID). XSCID is caused by mutations in the IL2RG gene encoding the interleukin receptor signaling gamma chain [gamma c]). The study population are older children (greater than or equal to 2 years of age) and adults (less than or equal to 40 years of age) who are experiencing deteriorating and/or dysfunctional immunity and any of a constellation of severe or chronic medical problems warranting transplantation. The study is designed to evaluate whether the use of uniquely designed transplant conditioning and graft-versus-host disease (GvHD) prevention regimens achieve sufficient engraftment of donor hematopoietic stem cells (HSCs) to facilitate robust restoration of cellular immunity (T cell/NK cell number and function) including thymic function, and humoral immunity (B cell number and function) while at the same time enhancing tolerance of the donor graft in a fashon that reduces the occurrence of GvHD but not at significantly enhancing the risk of post-transplant virus infection. One target population are XSCID patients who received matched sibling or haploidentical lymphocyte-depleted transplants as infants with little or no myeloid conditioning, resulting in variable restoration of T cell immunity, but little or no restoration of NK or B cell immunity. Another target population are XSCID patients with partial production or function of gamma c or XSCID patients with clonal somatic reversion of the mutation in the IL2RG gene, who have less severe immune deficiency in childhood. A subset of patients from all of these target XSCID populations may experience progressive deterioration of immune function leading to acute and chronic medical problems that warrant consideration of allogeneic or MUD transplant to restore immunity.
The conditioning and GvHD prevention regimens for this HSC transplant protocol are designed to use mobilized peripheral blood stem cells (PBSC) or bone marrow (BM) (if mobilization is not possible) from either an HLA-matched related sibling donor (alloPBSC) as first choice or from an HLA matched unrelated donor (MUD) for those without an appropriate HLA-matched related sibling donor. If there is no appropriately matched sibling donor nor MUD adult donor available, then an appropriately matched cord blood from the cord blood registries may be used for small children XSCID recipients. For the alloPBSC (or alloBM) transplantation (referred to as Group 1), we propose using a busulfan-based, nonmyeloablative conditioning regimen combined with horse Anti-human Thymocyte Globulin (h-ATG) immune suppression conditioning plus post-transplant sirolimus for tolerance inducing immunosuppressant to prevent GvHD. For the MUD or unrelated cord blood transplantation (referred to as Group 2), we will use a similar conditioning regimen, with a few modifications that include addition of total body irradiation with shielding and reduction in busulfan dosing, changes designed to address the increased risk of graft rejection with HLA-matched but unrelated donor HSC.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Early Phase 1|
|Study Design ICMJE||Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Inherited Immune Deficiencies|
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Enrollment ICMJE
|Actual Study Completion Date ICMJE||November 1, 2019|
|Actual Primary Completion Date||November 1, 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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): 3 significant new or chronic active infections during the 2 years preceding evaluation for enrollment, with each infection accounting for one criteria.
Infections are defined as an objective sign of infection (fever >38.30C [1010F] 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.)
ii. Chronic pulmonary disease as defined by:
iii. Gastrointestinal enteropathy:
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: . 3rd percentile for age
vii. Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists of 10 lesions or there are two or more lesions at each of two or more widely separated anatomic sites; or there are 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)
ix. Hypogammaglobulinemia: requires regular IgG supplementation
Ages 2 years 40 years.
HLA-matched family donor available or an HLA matched unrelated PBSC graft (10/10 or 9/10 mismatch) available, or a minimum of 4/6 HLA matched cord blood product. (If the size of the cord blood graft is less than 3.0 x 10(7) cells, a second appropriate 4/6 or greater match cord blood product must be available).
Must be HIV negative.
Must be able to stay within one hour s travel of the NIH for the first 3 months after transplantation and have a family member or other designated companion to stay with during the post transplant period.
Must provide a durable power of attorney for health care decisions to an appropriate adult relative or guardian in accordance to NIH -200 NIH Durable Power of Attorney for Health Care Decision Making.
If of child-bearing potential, must agree to consistently use contraception throughout study participation and for 3 months post-study. Acceptable forms of contraception are:
|Ages ICMJE||2 Years to 40 Years (Child, Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00426517|
|Other Study ID Numbers ICMJE||070075
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||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||November 1, 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP