Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA4 Deficiencies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04377867
Recruitment Status : Recruiting
First Posted : May 6, 2020
Last Update Posted : May 8, 2020
Sponsor:
Collaborator:
The Scientific and Technological Research Council of Turkey
Information provided by (Responsible Party):
Marmara University

Brief Summary:
Primary immune deficiencies (PID) are a group of chronic diseases characterized by recurrent infections. Apart from recurrent infections, in some of PIDs autoimmunity, allergy or malignancy could be accompanied to the diseases. Recently, the advanced sequencing technologies have led to the identification of a growing number of novel PIDs including the immune dysregulation syndromes caused by loss of function mutations in the LRBA (encoding lipopolysaccharide-responsive beige like anchor protein) and CTLA4 (encoding cytotoxic T lymphocyte antigen 4) genes, which are in common associated with autoimmunity in addition to a predisposition to recurrent infections. PIDs with autoimmune components usually tend to have a more protracted clinical course and poorer prognosis rendering early diagnosis and treatment more crucial. The accurate diagnosis largely relies on the molecular diagnosis due to the significant overlaps between the phenotypic expression of these various genetic defects. The project aims to provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and advanced immunological, genetic and molecular assays and rendering an early targeting therapy for patients, discover disease related new pathways and biomarkers that can be helpful during diagnosis and monitoring abatacept targeted therapy responses.

Condition or disease Intervention/treatment
LRBA Deficiency CTLA4 Haploinsufficiency Drug: Abatacept Injection [Orencia]

Detailed Description:

Lipopolysaccharide-responsive beige-like anchor (LRBA) and cytotoxic T lymphocyte protein-4 (CTLA-4) deficiencies are primary immunodeficiency characterized by recurrent sinopulmonary infections with hypogammaglobulinemia, lymphoproliferation and immunodysregulation, which presents by enteropathy, cytopenias and autoimmune endocrinopathy. LRBA plays a pivotal role in the intracellular trafficking of by CTLA4 re-routing it away from lysosomal degradation and back to the cell surface. CTLA-4 is an key immune checkpoint protein that is constitutively expressed on fork-head box P3 (FOXP3)+ regulatory T (Treg) cells and is also induced upon activation of conventional T cells. LRBA deficiency results in very low CTLA4 expression, which explains the phenotypic overlap between LRBA and CTLA4 deficient subjects. Furthermore, reduced Treg cells number and function have been demonstrated in LRBA-deficient patients. Consequent upon this, LRBA deficiency may manifest as an IPEX like disease with early onset autoimmunity.

LRBA was originally described as a common variable immune deficiency (CVID)-like disease with autoimmunity. To date, different agents have been applied in the treatment of LRBA and CTLA4 deficiencies, including corticosteroids, intravenous immunoglobulin therapy (IVIG), sirolimus, infliximab, rituximab and azathioprine. Some patients also benefit from hematopoietic stem cell transplantation (HSCT), which can be curative. More recently, studies have suggested the effectiveness of abatacept, a CTLA4-Ig fusion protein, in controlling disease-related immune dysregulatory phenotypes. In addition, some biomarkers like soluble CD25 and circulating T Follicular helper (cTFH) cells were described as useful to monitor patients' disease activity. Nevertheless, the long-term effectiveness of abatacept is not well documented. Also, there is no established consensus as to the dose and frequency of abatacept therapy for the treatment of those diseases and which biomarker is most reliable for follow up of patients.

Aims of this current study include:

  1. Provide better and early diagnosis for LRBA, CTLA4 deficiencies by using basic and advanced immunological, genetic and molecular assays and rendering an early targeting therapy for patients.
  2. Discover disease related new pathways and biomarkers that can be helpful during diagnosis and monitoring abatacept targeted therapy responses.

Layout table for study information
Study Type : Observational [Patient Registry]
Estimated Enrollment : 30 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 2 Years
Official Title: Identification of New Immunopathogenic Mechanisms Associated With LRBA or CTLA4 Deficiencies
Actual Study Start Date : January 15, 2020
Estimated Primary Completion Date : July 15, 2022
Estimated Study Completion Date : January 15, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Abatacept

Group/Cohort Intervention/treatment
LRBA deficient patients on abatacept
These patients will prospectively followed and biological samples collected at baseline as well as periodically every 3 months under therapy. Abatacept will be provided on an off-label basis upon approval of the physician's request of the drug by Turkish Medicines and Medical Devices Agency (TMMDA) of Turkish Ministry of Health. The dosage and interval of the drug is determined according to drug instructions provided by the drug company based on the weight of the patients.
Drug: Abatacept Injection [Orencia]
Patients on abatacept to control disease symptoms

CTLA4 haploinsufficient patients on abatacept
These patients will prospectively followed and biological samples collected at baseline as well as periodically every 3 months under therapy. Abatacept will be provided on an off-label basis upon approval of the physician's request of the drug by Turkish Medicines and Medical Devices Agency (TMMDA) of Turkish Ministry of Health. The dosage and interval of the drug is determined according to drug instructions provided by the drug company based on the weight of the patients.
Drug: Abatacept Injection [Orencia]
Patients on abatacept to control disease symptoms

Control group
Age matched healthy control group will be used during the study to determine the reference values of the immunological assays.



Primary Outcome Measures :
  1. Clinical Efficacy of abatacept in normalizing symptoms of disease [ Time Frame: 3-9 months ]
    The symptoms including lymphoproliferation, autoimmunity and chronic diarrhea should be controlled.

  2. Clinical tolerability of abatacept in patients [ Time Frame: 1-24 months ]
    Drug related side effects should not be observed (Severe viral or bacterial infections)


Secondary Outcome Measures :
  1. Discontinuation of other immunosuppressants [ Time Frame: 3-12 months ]
    Drug used before and after abatacept should be minimized


Biospecimen Retention:   Samples With DNA
Peripheral blood mononuclear cells, Serum, Plasma, Stool


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   1 Year to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Primary immune deficiencies characterized by immunodyregulatory diseases (LRBA and CTLA4 deficiencies). Age matched healthy individuals.
Criteria

Inclusion Criteria:

  • Patients diagnosed with LRBA and CTLA4 deficiencies and eligible for the study
  • Patients accept consent to participate in this study and followed prospectively on abatacept treatment.

Exclusion Criteria:

  • History of hypersensitivity to abatacept
  • History of acquired immunodeficiency diseases like HIV
  • EBV viremia during the study screening
  • Documented malignancy
  • Current active infectious disease (bacterial or fungal) like tuberculosis
  • Chronic hepatitis B or hepatitis C infections

Information from the National Library of Medicine

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): NCT04377867


Contacts
Layout table for location contacts
Contact: Safa Baris, M.D. +905052614986 safabaris@hotmail.com

Locations
Layout table for location information
Turkey
Marmara University Recruiting
Istanbul, Pendik, Turkey, 34903
Contact: Safa Baris, M.D.    05052614986    safabaris@hotmail.com   
Sponsors and Collaborators
Marmara University
The Scientific and Technological Research Council of Turkey
Investigators
Layout table for investigator information
Study Director: Safa Baris, M.D. Marmara University
Publications:
Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Rivière JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Pérez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarström L, Dogu F, Haskologlu S, İkincioğulları AI, Köstel Bal S, Baris S, Kilic SS, Karaca NE, Kutukculer N, Girschick H, Kolios A, Keles S, Uygun V, Stepensky P, Worth A, van Montfrans JM, Peters AMJ, Meyts I, Adeli M, Marzollo A, Padem N, Khojah AM, Chavoshzadeh Z, Avbelj Stefanija M, Bakhtiar S, Florkin B, Meeths M, Gamez L, Grimbacher B, Seppänen MRJ, Lankester A, Gennery AR, Seidel MG; Inborn Errors, Clinical, and Registry Working Parties of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiencies. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. J Allergy Clin Immunol. 2020 May;145(5):1452-1463. doi: 10.1016/j.jaci.2019.12.896. Epub 2019 Dec 27.

Layout table for additonal information
Responsible Party: Marmara University
ClinicalTrials.gov Identifier: NCT04377867    
Other Study ID Numbers: 09.2018.624
First Posted: May 6, 2020    Key Record Dates
Last Update Posted: May 8, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents