Severe Combined Immunodeficiency SyndromePhase 1NCT00018018
Gene Transfer Therapy for Severe Combined Immunodeficieny Disease (SCID) Due to Adenosine Deaminase (ADA) Deficiency
A Phase 1 study testing CD34+ cells transduced with ADA retrovir in people with Severe Combined Immunodeficiency Syndrome, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial summary
This study will evaluate a new method for delivering gene transfer therapy to patients with severe combined immunodeficiency disease (SCID) due to a defective adenosine deaminase (ADA) gene. Read more about this study
- Who is it for?
- Ages 1 month and older
- Conditions the study is for
- Severe Combined Immunodeficiency Syndrome
- What is being tested?
- CD34+ cells transduced with ADA retrovir
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Jun 2001to 17 Sep 2014
- 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 1 month and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients will be enrolled into this study if they fulfill the following three criteria:
- Patients of age greater than or equal to 1 month with a diagnosis of ADA-deficiency based on:
- Confirmed absence (less than 3% of normal levels) of ADA enzymatic activity in peripheral blood or (for neonates) umbilical cord erythrocytes and/or leukocytes, or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of enzyme replacement therapy.
- AND
- Evidence of severe combined immunodeficiency based on either:
- Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency
Show all 16Show fewer
- OR
- Evidence of severe immunologic deficiency in subject based on lymphopenia (absolute lymphocyte count less than 200) or severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (cpm less than 5,000) prior to institution of immune restorative therapy
- OR
- Evidence of genetic mutations affecting the ADA gene as determined by the CLIA certified laboratory and clinical evidence of combined immunodeficiency based on lymphopenia (absolute lymphocyte counts less than 2SD of age-matched control values) and hypogammaglobulinemia (less than 2SD of age-matched control values) or lack of specific antibody response to vaccination. Evidence of life-threatening illness (increased frequency and/or severity of infections resulting in hospitalization and/or the administration of intravenous antibiotics) is necessary for patients to be eligible under this criterion.
- Patients ineligible for allogeneic (matched sibling) bone marrow transplantation (BMT) based on:
- Absence of a medically eligible HLA-identical sibling with normal immune function who may serve as an allogenic bone marrow donor
- OR
- Election by the parents or the adult patients to forgo allogeneic BMT in favor of PEG-ADA enzyme therapy after being invited to discuss alternative treatment options with a physician not connected with the protocol.
- Written informed consent according to guidelines of the NHGRI IRB, NIH or the Committee on Clinical Investigations (CCI) at Children's Hospital Los Angeles (CHLA).
- This study is also open to delayed/late onset ADA-deficient patients who fulfill the criteria A, B.1, and C and who are not receiving PEG-ADA treatment after being invited to discuss all alternative treatment options with a physician not connected with the protocol.
Who cannot join
- Age:
- Age less than 1 month
- Hematologic:
- Anemia (hemoglobin less than 10.5 mg/dl, for subjects 2 years of age or less or hemoglobin less than 11.5 mg/dl for subjects older than 2 years of age in the presence of normal iron studies).
- Neutropenia
- absolute granulocyte count <500/mm (3) or
Show all 39Show fewer
- absolute granulocyte count 500-999/mm (3) (ages 1-12 months) or 500-1,499/mm (3) for ages >1 year) and bone marrow studies showing myelodysplasia or other gross abnormalities.
- Thrombocytopenia (platelet count less than 150,000 mm(3) at any age)
- PT or PTT greater than 2 times normal.
- Cytogenic abnormalities on peripheral blood.
- Infectious:
- Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, CMV or parvovirus B19 by DNA PCR at time of assessment.
- Pulmonary:
- Resting O2 saturation by pulse oximetry less than 95%.
- Chest X-ray indicating active or progressive pulmonary disease.
- Cardiac:
- Abnormal electrocardiogram (EKG) indicating cardiac pathology.
- Uncorrected congenital cardiac malformation.
- Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, or hypotension.
- Neurologic:
- Significant neurologic abnormality by examination.
- Uncontrolled seizure disorder.
- Renal:
- Renal insufficiency: for pediatric patients serum creatinine greater than or equal to 1.2 mg/dl, or greater than or equal to 3+ proteinuria, for adults values at grades greater than or equal to of the NCI Common Toxicity Criteria (CTC).
- Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by DAIDS Toxicity Scale or NCI CTC.
- Hepatic/Gl:
- Serum transaminases greater than 5 times normal.
- Serum bilirubin greater than 3.0 mg/dl.
- Serum glucose greater than 250 mg/dl.
- Intractable severe diarrhea.
- Oncologic:
- Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP)
- General:
- Expected survival less than 6 months.
- Major congenital anomaly.
- Subject pregnant.
- Medically eligible HLA-identical sibling available.
- Known hypersensitivity to busulfan.
- Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate infusion of transduced cells or ability to follow protocol.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Treatment of SCID Due to ADA Deficiency With Autologous Cord Blood or Bone Marrow CD34+ Cells Transduced With a Human ADA Gene
This study will evaluate a new method for delivering gene transfer therapy to patients with severe combined immunodeficiency disease (SCID) due to a defective adenosine deaminase (ADA) gene. This gene codes for the adenosine deaminase enzyme, which is essential for the proper growth and function of infection-fighting white blood cells called T and B lymphocytes. Patients who lack this enzyme are vulnerable to frequent and severe infections.
Some patients with this disease receive enzyme replacement therapy with weekly injections of the drug PEG-ADA (ADAGEN). This drug may increase the number of immune cells and reduce infections, but it is not a cure. Gene transfer therapy, in which a normal ADA gene is inserted into the patient s cells, attempts to correct the underlying cause of disease. This therapy has been tried in a small number of patients with varying degrees of success. In this study, the gene will be inserted into the patient s stem cells (cells produced by the bone marrow that mature into the different blood components white cells, red cells and platelets).
Read more
Patients with ADA deficiency and SCID who are taking PEG-ADA and are not candidates for HLA-identical sibling donor bone marrow transplantation may be eligible for this study.
Participants will be admitted to the NIH Clinical Center for 2 to 3 days. Stem cells will be collected either from cord blood (in newborn patients) or from the bone marrow. The bone marrow procedure is done under light sedation or general anesthesia. It involves drawing a small amount of marrow through a needle inserted into the hip bone. The stem cells in the marrow will be grown in the laboratory and a normal human ADA gene will be transferred into them through a special type of disabled mouse virus. A few days later, the patient will receive the ADA-corrected cells through an infusion in the vein that will last from 10 minutes to 2 hours.
Patients will be evaluated periodically for immune function with blood tests, skin tests, and reactions to tetanus, diphtheria, H. influenza B and S. pneumoniae vaccinations. The survival of ADA-corrected cells will be monitored through blood tests. The number and amount of blood tests will depend on the patient s age, weight and health, but is expected that blood will not be drawn more than twice a month. Patients will also undergo bone marrow biopsy aspirate (as described above) twice a year. Patients will be followed once a year indefinitely to evaluate the long-term effects of therapy.
Read the detailed description
This is a clinical gene transfer study that aims to verify the safety and efficacy of the use of retroviral vectors to introduce the human adenosine deaminase (ADA) gene into the hematopoietic progenitors of patients affected with severe combined immunodeficiency due to ADA deficiency. In addition, this protocol will examine the effects of the ADA gene transfer on the immune system of treated patients. Patients with ADA deficiency and ineligible for matched sibling allogeneic bone marrow transplantation are eligible to participate to the study. To increase engraftment and selective advantage of gene-corrected cells, busulfan will be used as cytoreduction agent and enzyme replacement (PEG-ADA) therapy will be discontinued. CD34+ hematopoietic progenitors will be isolated from the patient bone marrow or cord blood, exposed to retroviral vector-mediated gene transfer and reinfused into the patient through a peripheral vein. Clinical, immunological and molecular follow-up studies will assess safety, toxicity, and efficacy of the procedure.
- Being tested
- CD34+ cells transduced with ADA retrovir
- Keywords
- Gene Therapy, ADA-SCID, Stem Cells, Retroviruses, Immune Deficiency Disease, Adenosine Deaminase Deficiency, ADA-Deficiency, Retroviral Vectors, Hematopoietic Progenitors, Severe Combined Immunodeficiency, SCID, Immune Deficiency
- Medical subject headings
- Severe Combined Immunodeficiency, Severe combined immunodeficiency due to adenosine deaminase deficiency, Immune Deficiency Disease, Immunologic Deficiency Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CD34+ cells transduced with ADA retrovirDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jun 2001 (estimated)
- Study start20 Jun 2001
- Study completion17 Sep 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Severe Combined Immunodeficiency SyndromeStudies 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
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Robert A Sokolic, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00018018
- Sponsor's protocol ID
- 010189
- Other IDs
- 01-HG-0189
- Status last verified
- 17 Sep 2014
- First submitted
- 27 Jun 2001
- Last updated
- 12 Dec 2019
- Results posted
- No
Publications
Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968 Dec 28;2(7583):1366-9. doi: 10.1016/s0140-6736(68)92673-1. No abstract available.
PubMed 4177932Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972 Nov 18;2(7786):1067-9. doi: 10.1016/s0140-6736(72)92345-8. No abstract available.
PubMed 4117384Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies. N Engl J Med. 1995 Aug 17;333(7):431-40. doi: 10.1056/NEJM199508173330707. No abstract available.
PubMed 7616993Sokolic R, Maric I, Kesserwan C, Garabedian E, Hanson IC, Dodds M, Buckley R, Issekutz AC, Kamani N, Shaw K, Tan B, Bali P, Hershfield MS, Kohn DB, Wayne AS, Candotti F. Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency. Blood. 2011 Sep 8;118(10):2688-94. doi: 10.1182/blood-2011-01-329359. Epub 2011 Jul 1.
PubMed 21725047
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of SCID Due to ADA Deficiency With Autologous Cord Blood or Bone Marrow CD34+ Cells Transduced With a Human ADA Gene
- ClinicalTrials.gov ID
- NCT00018018
- Acronym / sponsor ID
- 010189
- Keywords
- Gene Therapy, ADA-SCID, Stem Cells, Retroviruses, Immune Deficiency Disease, Adenosine Deaminase Deficiency, ADA-Deficiency, Retroviral Vectors
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Study start
- 20 Jun 2001
- Study completion
- 17 Sep 2014 (actual)
- First posted
- 28 Jun 2001 (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.
This study will evaluate a new method for delivering gene transfer therapy to patients with severe combined immunodeficiency disease (SCID) due to a defective adenosine deaminase (ADA) gene. This gene codes for the adenosine deaminase enzyme, which is essential for the proper growth and function of infection-fighting white blood cells called T and B lymphocytes. Patients who lack this enzyme are vulnerable to frequent and severe infections.
Some patients with this disease receive enzyme replacement therapy with weekly injections of the drug PEG-ADA (ADAGEN). This drug may increase the number of immune cells and reduce infections, but it is not a cure. Gene transfer therapy, in which a normal ADA gene is inserted into the patient s cells, attempts to correct the underlying cause of disease. This therapy has been tried in a small number of patients with varying degrees of success. In this study, the gene will be inserted into the patient s stem cells (cells produced by the bone marrow that mature into the different blood components white cells, red cells and platelets).
Patients with ADA deficiency and SCID who are taking PEG-ADA and are not candidates for HLA-identical sibling donor bone marrow transplantation may be eligible for this study.
Participants will be admitted to the NIH Clinical Center for 2 to 3 days. Stem cells will be collected either from cord blood (in newborn patients) or from the bone marrow. The bone marrow procedure is done under light sedation or general anesthesia. It involves drawing a small amount of marrow through a needle inserted into the hip bone. The stem cells in the marrow will be grown in the laboratory and a normal human ADA gene will be transferred into them through a special type of disabled mouse virus. A few days later, the patient will receive the ADA-corrected cells through an infusion in the vein that will last from 10 minutes to 2 hours.
Patients will be evaluated periodically for immune function with blood tests, skin tests, and reactions to tetanus, diphtheria, H. influenza B and S. pneumoniae vaccinations. The survival of ADA-corrected cells will be monitored through blood tests. The number and amount of blood tests will depend on the patient s age, weight and health, but is expected that blood will not be drawn more than twice a month. Patients will also undergo bone marrow biopsy aspirate (as described above) twice a year. Patients will be followed once a year indefinitely to evaluate the long-term effects of therapy.
Detailed description
This is a clinical gene transfer study that aims to verify the safety and efficacy of the use of retroviral vectors to introduce the human adenosine deaminase (ADA) gene into the hematopoietic progenitors of patients affected with severe combined immunodeficiency due to ADA deficiency. In addition, this protocol will examine the effects of the ADA gene transfer on the immune system of treated patients. Patients with ADA deficiency and ineligible for matched sibling allogeneic bone marrow transplantation are eligible to participate to the study. To increase engraftment and selective advantage of gene-corrected cells, busulfan will be used as cytoreduction agent and enzyme replacement (PEG-ADA) therapy will be discontinued. CD34+ hematopoietic progenitors will be isolated from the patient bone marrow or cord blood, exposed to retroviral vector-mediated gene transfer and reinfused into the patient through a peripheral vein. Clinical, immunological and molecular follow-up studies will assess safety, toxicity, and efficacy of the procedure.
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 1 month and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (16 listed)
- Patients of age greater than or equal to 1 month with a diagnosis of ADA-deficiency based on:
- Confirmed absence (less than 3% of normal levels) of ADA enzymatic activity in peripheral blood or (for neonates) umbilical cord erythrocytes and/or leukocytes, or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of enzyme replacement therapy.
- AND
- Evidence of severe combined immunodeficiency based on either:
- Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency
Key exclusion criteria (39 listed)
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 |
|---|---|---|
| CD34+ cells transduced with ADA retrovir | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Dec 2019.
- Background: PubMed 4177932Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968 Dec 28;2(7583):1366-9. doi: 10.1016/s0140-6736(68)92673-1. No abstract available.
- Background: PubMed 4117384Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972 Nov 18;2(7786):1067-9. doi: 10.1016/s0140-6736(72)92345-8. No abstract available.
- Background: PubMed 7616993Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies. N Engl J Med. 1995 Aug 17;333(7):431-40. doi: 10.1056/NEJM199508173330707. No abstract available.
- Derived from this study: PubMed 21725047Sokolic R, Maric I, Kesserwan C, Garabedian E, Hanson IC, Dodds M, Buckley R, Issekutz AC, Kamani N, Shaw K, Tan B, Bali P, Hershfield MS, Kohn DB, Wayne AS, Candotti F. Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency. Blood. 2011 Sep 8;118(10):2688-94. doi: 10.1182/blood-2011-01-329359. Epub 2011 Jul 1.
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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.
Robert A Sokolic, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
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 CD34+ cells transduced with ADA retrovir in people with Severe Combined Immunodeficiency Syndrome, run by National Human Genome Research Institute (NHGRI) 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 16 inclusion and 39 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 12 Dec 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 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?
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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00018018, which also lists 4 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 12 Dec 2019.