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Inherited Immune DeficienciesEarly Phase 1NCT00426517

Donor Stem Cell Transplantation for Congenital Immunodeficiencies

A Early Phase 1 study testing Campath 1H, Busulfan and Horse Anti-human Thymocyte Globulin (h-ATG) in people with Inherited Immune Deficiencies, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 2 to 40 years
Conditions the study is for
Inherited Immune Deficiencies
What is being tested?
Campath 1H, Busulfan and Horse Anti-human Thymocyte Globulin (h-ATG)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
48 participants
Where
1 siteUnited States
Study dates
19 Jan 2007to 1 Nov 2019
Phase
Early Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 2 to 40 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • PATIENTS (RECIPIENT)
  • Must have confirmed genetic diagnosis of XSCID (common gamma chain disorder) by identification of a mutation in the IL2RG gene or by demonstrating failure to detect gamma c protein in patient immune blood cells.
  • Must have sufficient complications from underlying disease to warrant undergoing transplantation as defined as follows:.
  • Clinical Criteria: (greater than or equal to 1 must be present)
  • 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.)
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  • Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics . 14 days OR
  • Hospitalization of any duration for infection OR
  • 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
  • Chronic pulmonary disease as defined by:
  • Bronchiectasis by x-ray computerized tomography OR
  • Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is . 60% of Predicted for Age OR
  • Pulse oximetry . 94% in room air (if patient is too young to comply with performance of PFTs).
  • Gastrointestinal enteropathy:
  • Diarrhea-watery stools . 3 times per day (of at least 3 months duration that is not a result of infection as defined in criterion # i. above) OR
  • Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated) OR
  • 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).
  • Poor nutrition: Requires G-tube or intravenous feeding supplement to maintain weight or nutrition.
  • 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.
  • Failure to grow in height: . 3rd percentile for age
  • 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)
  • Mucocutaneous candidiasis (chronic oral thrush or candida esophagitis or candida intertriginous infection or candida nail infections; must be culture positive to satisfy this criterion)
  • 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:
  • Condoms, male or female, with or without a spermicide
  • Diaphragm or cervical cap with spermicide
  • Intrauterine device
  • Contraceptive pills or patch, Norplant, Depo-Provera, or other FDA-approved contraceptive method
  • Male partner has previously undergone a vasectomy

Who cannot join

  • PATIENT (RECIPIENT)
  • Eastern Cooperative Oncology Group (ECOG) or equivalent performance status of 3 or more (See Supportive Care guidelines, available at http://intranettst2.cc.nih.gov/bmt/clinicalcare).
  • Left ventricular ejection fraction less than 40%.
  • Transaminases greater than 5 times upper limit of normal based on the patient s clinical situation and at the discretion of the investigator.
  • Liver alkaline phosphatase >10x upper limit of normal based on the patient's clinical situation and at the discretion of the investigator
  • Psychiatric disorder or mental deficiency severe enough as to make compliance with the BMT treatment unlikely, and/or making informed consent impossible.
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  • Major anticipated illness or organ failure incompatible with survival from AlloPBSC, MUD or unrelated cord blood transplant
  • Pregnant or lactating.
  • HIV positive.
  • Uncontrolled seizure disorder.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: 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.

Read more

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:

  1. A severe immune deficiency, such as chronic granulomatous disease or leukocyte adhesion deficiency.
  2. Have problems from the disease that call for stem cell transplantation.
  3. You must also be between the ages of 2 and 40 years.

Two groups of patients are included in this study:

  1. Patients who have a brother or sister that have stem cells that match the patient. This is known as an allogeneic matched sibling transplant.
  2. Patients who do not have a matched sibling donor but have a donor that matches in the National Marrow Donor Program. This is know as matched unrelated donor transplantation.

Patients will have the following procedures:

  • To create space in the bone marrow, patients are given two drugs, Campath-1H and busulfan. To prevent the body from getting rid of the donated cells, patients are given sirolimus. On the day before the BMT, patients in the matched unrelated donor group also receive a low-dose of whole-body radiation. This will further improve the chances that the patients body will accept the donor cells.
  • Patients will get the donor stem cells through an intravenous (IV) line that goes into a vein in their body. The cells make their way to the bone marrow space and slowly refill the marrow over the next several weeks. Patients will usually stay in the hospital for 30 days after the transplant.
  • For the first 3 months after the transplant, patients are watched closely. The patients will have frequent visits to the clinic. During these visits the patient will have a physical examination and blood tests. The doctor and nurse will also check any symptoms the patient may have. At day 100 after the transplant a sample of bone marrow is taken.
  • Patients will continue to be followed periodically for at least 5 years after the transplant.
Read the detailed description

This is an open-label pilot study of HLA-matched allogenic 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 fashion 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.

Being tested
Campath 1H, Busulfan, Horse Anti-human Thymocyte Globulin (h-ATG), Total Body Irradiation (TBI), Sirolimus or equivalent based on response
Keywords
MUD Transplant, Transplant, AlloPBSC, HLA Matched Transplant, BMT, Congenital Immunodeficiency, Bone Marrow Transplant

What participants receive

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

  • Campath 1HDrug

    Also called alemtuzumab

    Conditioning with Campath 1 mg/kg total dose given intravenously over 5 days

  • BusulfanDrug

    Also called Busulfex® (IV formulation)

    Busulfan 5-10 mg/kg total dose given intravenously over 2 days based on patient underlining immune deficiency disorder

  • Horse Anti-human Thymocyte Globulin (h-ATG)Drug

    Also called ATG

    Conditioning with h-ATG 40 mg/kg total dose over 4 days given intravenously

  • Total Body Irradiation (TBI)Drug

    Also called TBI

    TBI 200 - 300 centigray (cGy) in two fractions at day -2 or same day depending on patient underlining immune deficiency disorder

  • Sirolimus or equivalent based on responseDrug

    Also called Rapamune®/rapamycin

    post Transplantation immunosuppressants

Study groups in NCT00426517
Study groupRoleWhat they receive
Matched related donor stem cell transplantExperimentalConditioning with Campath 1 mg/kg total dose given intravenously over 5 days, Busulfan 10 mg/kg total dose given intravenously over 2 days
Receives: Drug: Campath 1H; Drug: Busulfan; Drug: Sirolimus or equivalent based on response
Matched unrelated donor stem cell transplantExperimentalConditioning with Campath 1 mg/kg total dose given intravenously over 5 days, Busulfan 5 mg/kg total dose given intravenously over 2 days, and Total Body Irradiation (TBI) 200 cGy in two fractions on the same day
Receives: Drug: Campath 1H; Drug: Busulfan; Drug: Total Body Irradiation (TBI); Drug: Sirolimus or equivalent based on response
Matched unrelated donor stem cell transplant (MUD-non CGD)ExperimentalConditioning with ATG 40 mg/kg total dose over 4 days IV, Busulfan 5 mg/kg total dose over 2 days IV, and TBI 300 cGy in two fractions at day -2
Receives: Drug: Busulfan; Drug: Horse Anti-human Thymocyte Globulin (h-ATG); Drug: Total Body Irradiation (TBI); Drug: Sirolimus or equivalent based on response
Matched unrelated donor transplant (MUD-CGD) cord bloodExperimentalConditioning with Campath 1 mg/kg total dose given intravenously over 5 days, Busulfan 5 mg/kg total dose given intravenously over 2 days, and Total Body Irradiation (TBI) 200 cGy in two fractions on the same day
Receives: Drug: Campath 1H; Drug: Busulfan; Drug: Total Body Irradiation (TBI); Drug: Sirolimus or equivalent based on response

What is being measured

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

  1. Stem Cell Transplant Engraftment

    Engraftment of allogeneic or matched unrelated (including cord blood) hematopoietic progenitor cells using moderate-dose busulfan and Campath-1H with or without whole body irradiation so as to attain phenotypic correction of congenital immunodeficiencies.

    Measured: 1 year

Secondary outcomes (7)

  1. Engraftment Without Development of GVHD

    Participants who achieved engraftment without development of graft versus host disease (GVHD).

    Measured: 1 year

  2. Participants With Established Stable Mixed Chimerism

    Number of participants with myeloid chimerism of greater than 10% of donor cells at 1 year post transplant

    Measured: 1 year

  3. Days to CD3 Count Greater Than 100 u/L

    Rapidity of immune reconstitution based on number of days to CD3 count greater than 100 u/L.

    Measured: 1 year

  4. Days to Absolute Neutrophil Recovery (ANC)

    Recovery is defined as an absolute neutrophil count (ANC) of ≥ 0.5 x 109 /L (500/mm3 ) for three consecutive laboratory values obtained on different days. Date of ANC recovery is the date of the first of three consecutive laboratory values where the ANC is ≥ 0.5 x 109 /L.

    Measured: 1 year

  5. Number of RBC Transfusions Per Subject

    Average number of red blood cell (RBC) transfusion per subject

    Measured: 1 year

  6. Days to Platelet Recovery

    Platelet recovery is defined as platelet value ≥ 20 × 109/L for three consecutive days and no platelet transfusions administered for previous seven consecutive days. The date of platelet recovery is the date of the first of three consecutive laboratory values ≥ 20 × 109/L.

    Measured: 1 year

  7. Incidence of Cytomegalovirus (CMV) Disease

    Number of events of Cytomegalovirus disease based on clinical sequelae that requires treatment (not reactivation)

    Measured: 1 year

Timeline

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

  1. First posted24 Jan 2007 (estimated)
  2. Study start19 Jan 2007
  3. Primary completion1 Nov 2019
  4. Study completion1 Nov 2019

Resources

More details

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

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Factorial
Masking
None (open label)
Enrolment
48 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00426517
Sponsor's protocol ID
070075
Other IDs
07-I-0075
Status last verified
1 Nov 2019
First submitted
23 Jan 2007
Last updated
11 May 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, Notarangelo LD, Roifman CM. Bone marrow transplantation for severe combined immune deficiency. JAMA. 2006 Feb 1;295(5):508-18. doi: 10.1001/jama.295.5.508.

    PubMed 16449616

  • Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, Dickler H. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000 May;79(3):155-69. doi: 10.1097/00005792-200005000-00003.

    PubMed 10844935

  • Johnston RB Jr. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. 2001 Jan;8(1):17-22. doi: 10.1097/00062752-200101000-00004.

    PubMed 11138621

  • Roesler J, Brenner S, Bukovsky AA, Whiting-Theobald N, Dull T, Kelly M, Civin CI, Malech HL. Third-generation, self-inactivating gp91(phox) lentivector corrects the oxidase defect in NOD/SCID mouse-repopulating peripheral blood-mobilized CD34+ cells from patients with X-linked chronic granulomatous disease. Blood. 2002 Dec 15;100(13):4381-90. doi: 10.1182/blood-2001-12-0165. Epub 2002 Aug 1.

    PubMed 12393624

  • Kang EM, de Witte M, Malech H, Morgan RA, Phang S, Carter C, Leitman SF, Childs R, Barrett AJ, Little R, Tisdale JF. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood. 2002 Jan 15;99(2):698-701. doi: 10.1182/blood.v99.2.698.

    PubMed 11781257

  • Horwitz ME, Barrett AJ, Brown MR, Carter CS, Childs R, Gallin JI, Holland SM, Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001 Mar 22;344(12):881-8. doi: 10.1056/NEJM200103223441203.

    PubMed 11259721

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Campath 1H, Busulfan and Horse Anti-human Thymocyte Globulin (h-ATG) in people with Inherited Immune Deficiencies, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.

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 35 inclusion and 10 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: finished, as of the sponsor's last update on 11 May 2021. 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 States. 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?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

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

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 May 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Stem Cell Transplant Engraftment (time frame: 1 year). 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 NCT00426517, which also lists 6 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 11 May 2021.

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