Safety and Efficacy of Abatacept for Treating Chronic Cytopenia in Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Haploinsufficiency

NCT03733067 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: 19001519-I-0015
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background: 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. Objective: To see if abatacept is safe and helps treat cytopenias caused by CTLA4 deficiency. Eligibility: People ages 8-65 years who have CTLA4 deficiency with cytopenia Design: 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.

Conditions

CTLA4 Haploinsufficency; Chronic Cytopenia

Keywords

Regulatory T Cells; T-cell hyperactivation; Autoimmune Cytopenia; Adult Rheumatoid Arthritis; Juvenile Idiopathic Arthritis

Outcome Measures

Primary Outcomes (2)

• assess safety and tolerability of abacept given at double doses

  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.

  To be measured at day 210

• Clinical Efficacy of abatacept in normalizing cytopenias

  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/dLParameters 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.

  To be measured at day 210

Secondary Outcomes (2)

• measure of time to cytopenia recurrence

  From initiating the taper or discontinuation of concomitant medications while on treatment

• Clinical efficacy of abatacept in improving but not normalizing cytopenais

  To be measured at Day 210

Study Arms (2)

abatacept

EXPERIMENTAL

Adult and pediatric dosing will be based on weight per protocol

Drug: abatacept

placebo

PLACEBO COMPARATOR

will be given as the same IV volume as abatacept

Other: Placebo

Interventions

abatacept DRUG

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.

abatacept

Placebo OTHER

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

placebo

Eligibility Criteria

• Age: 8 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Individuals must meet all of the following criteria to be eligible for study participation:
• Age 8-65 years.
• Documented CTLA4 mutation (requires documentation of confirmed mutation via Sanger sequencing at a laboratory approved by the Clinical Laboratory Improvement Amendments \[CLIA\]).
• At least one of the following established hematologic abnormalities during the past 6 months (including results from outside CLIA-certified laboratories) prior to screening:
• ANC \< 750 cells/microL.
• Platelet count \< 75,000 cells/microL.
• Hemoglobin \< 7.5 g/dL.
• The above mentioned hematologic abnormalities should require active treatment with steroids, immunomodulatory agents (e.g., mycophenolate mofetil, cyclosporine, tacrolimus, mercaptopurine, methotrexate, sirolimus, high dose intravenous immunoglobulin \[IVIG\]), and/or other agents (e.g., TPO agonists) for at least 60 days prior to screening.
• The dose of any concomitant medication(s) aimed at treating cytopenia should be stable in the 60 days prior to screening. Stable is defined as:
• No new concomitant medications for cytopenia were initiated.
• No dose increase of the medication was required.
• Did not receive blood product transfusions within 30 days prior to screening.
• Did not receive abatacept within 60 days prior to screening.
• Did not receive rituximab within 3060 days of screening.
• Did not receive alemtuzumab at any time.

You may not qualify if:

• Patients meeting any of the following criteria are not eligible for this study:
• History of hypersensitivity to abatacept.
• Any live vaccines (including attenuated live vaccines) within 6 weeks of screening.
• History of acquired immunodeficiency diseases, including a positive HIV polymerase chain reaction (PCR) test result.
• Untreated chronic hepatitis B (positive PCR) or hepatitis C (positive PCR) infection. Patients with chronic hepatitis must be on medical treatment for at least 3 months before screening and have evidence of decreased viral loads after starting treatment.
• EBV viral load \> 4log on 2 or more laboratory checks greater than 1 month apart and within 6 months of screening.
• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of evidence of local recurrence or metastases.
• Current active infectious disease (bacterial or fungal) including evidence of tuberculosis (TB) infection as defined by a positive QuantiFERON TB-Gold test. Test results within the past 6 months will be accepted. If presence of latent TB is established, then treatment must be completed before the patient can be considered for enrollment. The patient may also be considered for enrollment after completing treatment of any other active bacterial or fungal infection.
• Contraindication to PFT or CT scan.
• Pregnancy or breastfeeding.
• Any condition that, in the opinion of the investigator, contraindicates participation in this study.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R, Husami A, Kissell D, Nortman S, Chaturvedi V, Haines H, Young LR, Mo J, Filipovich AH, Bleesing JJ, Mustillo P, Stephens M, Rueda CM, Chougnet CA, Hoebe K, McElwee J, Hughes JD, Karakoc-Aydiner E, Matthews HF, Price S, Su HC, Rao VK, Lenardo MJ, Jordan MB. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015 Jul 24;349(6246):436-40. doi: 10.1126/science.aaa1663.

  PMID: 26206937 BACKGROUND

• Lee S, Moon JS, Lee CR, Kim HE, Baek SM, Hwang S, Kang GH, Seo JK, Shin CH, Kang HJ, Ko JS, Park SG, Choi M. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allergy Clin Immunol. 2016 Jan;137(1):327-330. doi: 10.1016/j.jaci.2015.08.036. Epub 2015 Oct 21. No abstract available.

  PMID: 26478010 BACKGROUND

• Salman J, Ius F, Knoefel AK, Sommer W, Siemeni T, Kuehn C, Tudorache I, Avsar M, Nakagiri T, Preissler G, Hatz R, Greer M, Welte T, Haverich A, Warnecke G. Association of Higher CD4+ CD25high CD127low , FoxP3+ , and IL-2+ T Cell Frequencies Early After Lung Transplantation With Less Chronic Lung Allograft Dysfunction at Two Years. Am J Transplant. 2017 Jun;17(6):1637-1648. doi: 10.1111/ajt.14148. Epub 2017 Jan 24.

  PMID: 27931084 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Arthritis, Rheumatoid; Arthritis, Juvenile

Interventions

Abatacept

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins

Study Officials

• Gulbu Uzel, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 6, 2018
• First Posted: November 7, 2018
• Study Start: November 30, 2023
• Primary Completion: November 30, 2023
• Study Completion: November 30, 2023
• Last Updated: December 4, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)