Safety and Efficacy of Abatacept for Treating Chronic Cytopenia in Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Haploinsufficiency
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|ClinicalTrials.gov Identifier: NCT03733067|
Recruitment Status : Not yet recruiting
First Posted : November 7, 2018
Last Update Posted : December 1, 2021
CTLA4 stands for cytotoxic T-lymphocyte antigen-4. It is a protein the body makes naturally to check its immune system from attacking itself. Some people don t produce enough CTLA4 protein, causing problems due to overactive immune system such as big spleens, repeated lung infections, breathing problems, stomach and intestine symptoms as well as inflamed brain and nerve problems. Many have problems with their bone marrow causing low numbers of blood cells like platelets, red blood cells or white blood cells, which is called cytopenia. Researchers want to see if the drug abatacept can treat cytopenias by replacing the missing protein CTLA4.
To see if abatacept is safe and helps treat cytopenias caused by CTLA4 deficiency.
People ages 8-65 years who have CTLA4 deficiency with cytopenia
Participants will be screened with medical history, medication review, physical exam and blood and urine tests. They will continue their current medications and may start taking antibiotics daily. Participants will receive either abatacept or placebo through a vein for 6 months. The study team will not know if you are receiving the study drug or the placebo
Women who can become pregnant must agree to use birth control measures.
Men who get someone pregnant during the study will be asked to collect information and have the partner contact the study team.
Participants will undergo the following procedures before starting the study and at the completion:
- radiology scans of body and brain
- heart and lung function tests
- Bone marrow examination by a needle inserted into the hip bone to remove a small amount of tissue to study.
- Participants may have a small camera on a long, thin tool passed down the throat into the stomach and small intestine for evaluation of their gut.
- Questionnaires about their disease, symptoms and quality of life
Over 6 months, participants will have regular study visits and get 8 doses of the study drug or a placebo by intravenous injection. They will repeat some of the same tests done earlier at the end of the study at assess response.
About 1 month after the last study drug visit, participants will have a final study visit.
Some participants may join a treatment extension for the study drug abatacept with no placebo. They will sign a separate consent form for this.
|Condition or disease||Intervention/treatment||Phase|
|CTLA4 Haploinsufficency Chronic Cytopenia||Drug: abatacept Other: Placebo||Phase 1 Phase 2|
Rare heterozygous mutations in cytotoxic T-lymphocyte antigen-4 (CTLA4) lead to a monogenetic defect that presents with a heterogeneous clinical phenotype of recurrent infections, lymphoproliferation, autoimmunity, and lymphocytic infiltration of target organs. Management is challenging and focuses on treating infections, autoimmune complications, and end organ damage due to lymphocytic infiltrates. Experience with the natural history of the disease and therapies for underlying complications are limited. There is no established standard of care for these patients.
Abatacept is a biologically engineered CTLA4-mimetic that is approved as an intravenous (IV) infusion to treat adult rheumatoid arthritis, adult psoriatic arthritis, and juvenile idiopathic arthritis. Given that abatacept mimics CTLA4 function, we hypothesize that the drug will prevent T-cell hyper activation, restore regulatory T-cell function, and thereby treat the autoimmune and immune dysregulatory manifestations of CTLA4 deficiency.
This study is a phase 1/2, double-blind, randomized, intra-patient dose-escalation, placebo controlled trial designed to evaluate the safety and efficacy of abatacept in participants with CTLA4 deficiency and cytopenia. Participants will come to the NIH Clinical Center monthly for 210 days to receive infusions of study agent or placebo and to undergo safety and research evaluations, including blood draw for cytopenia evaluation and scoring of disease severity. Before and after the treatment period, participants will also have imaging, pulmonary function testing, bone marrow biopsy, and endoscopy (symptomatic participants only). Primary endpoints will be evaluated at Day 210. After completing the blinded treatment trial, participants will be offered the option to enroll in a 6-month open-label extension study for long term safety evaluation of abatacept.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Phase 1/2 Randomized, Double-Blind, Placebo-Controlled Study of Safety and Efficacy of Abatacept for Treating Chronic Cytopenia in Cytotoxic T-lymphocyte Antigen 4 (CTLA4) Haploinsufficiency|
|Estimated Study Start Date :||December 6, 2021|
|Estimated Primary Completion Date :||June 30, 2026|
|Estimated Study Completion Date :||June 30, 2026|
Adult and pediatric dosing will be based on weight per protocol
Double-blind, placebo-controlled, intra-patient dose-escalation trial of abatacept for treating cytopenia in CTLA4 deficiency. Abatacept or placebo will be administered for 3 doses over 30 days, followed by 5 more months of administration at double the initial dose. If the participant s hematologic parameters normalize at Day 120 or onwards, the investigator may taper or discontinue concomitant medications aimed at treating cytopenia.
Placebo Comparator: placebo
will be given as the same IV volume as abatacept
Saline packaged identically to abatacept, with volume matching that of the abatacept dosing by weight, and will be administered via IV infusion identically to abatacept
- assess safety and tolerability of abacept given at double doses [ Time Frame: To be measured at day 210 ]All safety parameters (including possibly to definitely related AEs and SAEs, physical exam, vital signs, ECG, safety laboratories [hematology, blood chemistry, urinalysis]) and incidence and severity of infections at initial and doubled doses of abatacept at Day 210.
- Clinical Efficacy of abatacept in normalizing cytopenias [ Time Frame: To be measured at day 210 ]A complete response defined by the normalization of all listed hematologic parameters:A) ANC > 1,000 cells/microliter; andB) Platelet count > 100,000 cells/microliter; andC) Hemoglobin > 10 g/dL.Parameters will be measured at Day 210 and must be met without any transfusions and concomitant medications (immunomodulatory therapy, exogenous growth factor, steroids, hematopoietic/TPO mimetic agent) aimed at treating cytopenias during the past 28 days.
- measure of time to cytopenia recurrence [ Time Frame: From initiating the taper or discontinuation of concomitant medications while on treatment ]
- Clinical efficacy of abatacept in improving but not normalizing cytopenais [ Time Frame: To be measured at Day 210 ]Partial hematologic response defined as an improvement in one or more of the listed parameters but not meeting complete hematologic response:A) ANC: a 100% increase from baseline or an ANC >= 750 cells/microL.B) Platelet: for baseline count >= 20,000/microL but < 75,000/microL: a 100% increase in platelet count or a platelet count > 75,000/ (Micro)L; for baseline platelet count < 20,000/micro: a 100% increase in platelet count or a platelet count > 20,000/microL.C) Any increase in hemoglobin by 2 g/dL.All of the parameters will be measured at Day 210 and must be met without any transfusions and concomitant medications (immunomodulatory therapy, exogenous growth factor, steroids, hematopoietic/TPO mimetic agent) aimed at treating cytopenias during the past 28 days. OR A normalization of hematologic parameters as defined in the primary endpoint AND a dose reduction or discontinuation of baseline concomitant medications.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03733067
|Contact: Katherine N Howe, P.A.-C||(240) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Gulbu Uzel, M.D.||National Institute of Allergy and Infectious Diseases (NIAID)|