LRBA DeficiencyNCT04377867
New Biomarkers for Diagnosis and Follow-up of Patients With LRBA or CTLA4 Deficiencies
An observational study of LRBA Deficiency and CTLA4 Haploinsufficiency, run by Marmara University at 1 site in Turkey (Türkiye).
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- LRBA Deficiency, CTLA4 Haploinsufficiency
- What is being tested?
- Abatacept Injection [Orencia]
- Type of treatment
- Injection or infusion
- How many people
- 30 participants
- Where
- 1 siteTurkey (Türkiye)
- Study dates
- 15 Jan 2020to 15 Jan 2023
- How long will I take part?
- 2 Years
- Phase
- Observational
- 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 year to 60 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Study population: Primary immune deficiencies characterized by immunodyregulatory diseases (LRBA and CTLA4 deficiencies). Age matched healthy individuals.
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Turkey (Türkiye)1 site, 1 recruiting
- Recruiting
Marmara University
Istanbul, Pendik, 34903
Safa Baris, M.D., 05052614986, safabaris@hotmail.com
About this study
Official title: Identification of New Immunopathogenic Mechanisms Associated With LRBA or CTLA4 Deficiencies
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.
Read the 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:
- 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.
- Conditions
- LRBA Deficiency, CTLA4 Haploinsufficiency
- Being tested
- Abatacept Injection [Orencia]
- Medical subject headings
- Diabetes Mellitus, Insulin-Dependent, 12
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Abatacept Injection [Orencia]Drug
Patients on abatacept to control disease symptoms
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Abatacept Injection [Orencia] | |
| 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. Receives: Drug: Abatacept Injection [Orencia] | |
| Control group | Age matched healthy control group will be used during the study to determine the reference values of the immunological assays. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical Efficacy of abatacept in normalizing symptoms of disease
The symptoms including lymphoproliferation, autoimmunity and chronic diarrhea should be controlled.
Measured: 3-9 months
Clinical tolerability of abatacept in patients
Drug related side effects should not be observed (Severe viral or bacterial infections)
Measured: 1-24 months
Secondary outcomes (1)
Discontinuation of other immunosuppressants
Drug used before and after abatacept should be minimized
Measured: 3-12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2020
- Study start15 Jan 2020
- Primary completion15 Jul 2022 (estimated)
- Study completion15 Jan 2023 (estimated)
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 LRBA DeficiencyStudies of the same condition, open and under way.
- More trials run by Marmara UniversityThe sponsor's other registered studies.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 30 participants (estimated)
- Target duration
- 2 Years
Sponsor and investigators
- Lead sponsor
- Marmara University
- Sponsor type
- University, hospital or other
- Collaborators
- The Scientific and Technological Research Council of Turkey
- Responsible party
- Sponsor
- Investigators
- Safa Baris, M.D., Study director, Marmara University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04377867
- Sponsor's protocol ID
- 09.2018.624
- Status last verified
- May 2020
- First submitted
- 3 May 2020
- Last updated
- 8 May 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, Dogruel D, Karaca NE, Cogurlu MT, Bilir OA, Cansever M, Kapakli H, Baser D, Kasap N, Kutlug S, Altintas DU, Al-Shaibi A, Agrebi N, Kara M, Guven A, Somer A, Aydogmus C, Ayaz NA, Metin A, Aydogan M, Uncuoglu A, Patiroglu T, Yildiran A, Guner SN, Keles S, Reisli I, Aksu G, Kutukculer N, Kilic SS, Yilmaz M, Karakoc-Aydiner E, Lo B, Ozen A, Chatila TA, Baris S. Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2790-2800.e15. doi: 10.1016/j.jaip.2019.06.011. Epub 2019 Jun 22.
PubMed 31238161Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, Algassim A, Keles S, Al Saud BK, Alkuraya FS, Jordan M, Geha RS, Chatila TA. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018 Mar;141(3):1050-1059.e10. doi: 10.1016/j.jaci.2017.05.022. Epub 2017 Jun 7.
PubMed 28601686Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Riviere JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Perez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarstrom L, Dogu F, Haskologlu S, Ikinciogullari AI, Kostel 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, Seppanen 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.
PubMed 31887391Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, Charbonnier LM, Bakir M, Boztug K, Chatila TA, Barlan IB. Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1. J Clin Immunol. 2016 Oct;36(7):641-8. doi: 10.1007/s10875-016-0312-3. Epub 2016 Jul 5.
PubMed 27379765
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification of New Immunopathogenic Mechanisms Associated With LRBA or CTLA4 Deficiencies
- ClinicalTrials.gov ID
- NCT04377867
- Acronym / sponsor ID
- 09.2018.624
- Conditions
- LRBA Deficiency, CTLA4 Haploinsufficiency
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Marmara UniversityUniversity, hospital or other
- Collaborators
- The Scientific and Technological Research Council of Turkey
- Study start
- 15 Jan 2020 (actual)
- Primary completion
- 15 Jul 2022 (estimated)
- Study completion
- 15 Jan 2023 (estimated)
- First posted
- 6 May 2020 (actual)
- 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.
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.
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:
- 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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 2 Years
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| LRBA deficient patients on abatacept | – | Drug: Abatacept Injection [Orencia]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. |
| CTLA4 haploinsufficient patients on abatacept | – | Drug: Abatacept Injection [Orencia]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. |
| Control group | – | –Age matched healthy control group will be used during the study to determine the reference values of the immunological assays. |
Who may qualify
- Ages
- 1 year to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- Study population
- Primary immune deficiencies characterized by immunodyregulatory diseases (LRBA and CTLA4 deficiencies). Age matched healthy individuals.
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (6 listed)
- 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
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 |
|---|---|---|
| Abatacept Injection [Orencia]Patients on abatacept to control disease symptoms | Drug | CTLA4 haploinsufficient patients on abatacept, LRBA deficient patients on abatacept |
Primary outcome
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.
Clinical tolerability of abatacept in patients
Time frame: 1-24 months
Drug related side effects should not be observed (Severe viral or bacterial infections)
1 secondary outcome
Discontinuation of other immunosuppressants
Time frame: 3-12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2020.
- Background: PubMed 31238161Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, Dogruel D, Karaca NE, Cogurlu MT, Bilir OA, Cansever M, Kapakli H, Baser D, Kasap N, Kutlug S, Altintas DU, Al-Shaibi A, Agrebi N, Kara M, Guven A, Somer A, Aydogmus C, Ayaz NA, Metin A, Aydogan M, Uncuoglu A, Patiroglu T, Yildiran A, Guner SN, Keles S, Reisli I, Aksu G, Kutukculer N, Kilic SS, Yilmaz M, Karakoc-Aydiner E, Lo B, Ozen A, Chatila TA, Baris S. Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2790-2800.e15. doi: 10.1016/j.jaip.2019.06.011. Epub 2019 Jun 22.
- Background: PubMed 28601686Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, Algassim A, Keles S, Al Saud BK, Alkuraya FS, Jordan M, Geha RS, Chatila TA. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018 Mar;141(3):1050-1059.e10. doi: 10.1016/j.jaci.2017.05.022. Epub 2017 Jun 7.
- Background: PubMed 31887391Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Riviere JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Perez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarstrom L, Dogu F, Haskologlu S, Ikinciogullari AI, Kostel 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, Seppanen 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.
- Background: PubMed 27379765Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, Charbonnier LM, Bakir M, Boztug K, Chatila TA, Barlan IB. Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1. J Clin Immunol. 2016 Oct;36(7):641-8. doi: 10.1007/s10875-016-0312-3. Epub 2016 Jul 5.
- Individual participant dataSharing planned: No
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.
Safa Baris, M.D. study director
Marmara University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of LRBA Deficiency and CTLA4 Haploinsufficiency, run by Marmara University at 1 site in Turkey (Türkiye).
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 2 inclusion and 6 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: status not confirmed, as of the sponsor's last update on 8 May 2020. 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 Turkey (Türkiye). 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.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Safa Baris, M.D. (+905052614986, safabaris@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical Efficacy of abatacept in normalizing symptoms of disease (time frame: 3-9 months). The study lists 2 primary outcomes in all. 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 NCT04377867, 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 8 May 2020.