Patients with a molecular confirmed diagnosis of CTLA4 (cytotoxic T-lymphocyte-associated Protein 4) (haplo)-insufficiency or LRBA (Lipopolysaccharide-Responsive and Beige-like An¬chor) deficiency MedDRA version: 20.1 Level: PT Classification code 10021449 Term: Immunodeficiency common variable System Organ Class: 10021428 - Immune system disorders
Conditions
Interventions
Trade Name: ORENCIA® Injektionslösung in einer Fertigspritze
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: ABATACEPT
CAS Number: 332348-12-6
Current Sponsor co
Sponsors
Universitätsklinikum Freiburg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Molecular diagnosis of CTLA4 (haplo)-insufficiency or LRBA deficiency with either published mutations or mutations with proven functional effect (impaired CTLA4 staining or CTLA4-dependent transendocytosis). 2. Age =18 years. 3. IgG serum trough level = 4 g/l (+/- IRT): last test result within 3 months at baseline visit. 4. Signed written informed consent. 5. Need for intervention on clinical grounds or continued need of therapy with abatacept as evaluated by the treating physician. 6. One organ system has to be involved. Organ involvements are defined as followed. In case of pretreatment with abatacept, organ involvement should be defined using retrospective data from the period before first application of abatacept. Patients with lung involvement: • typical radiographic features of GLILD in chest CT scan AND/OR • Lung function impairment (e.g. reduced TLC, FVC, reduced DLCO, reduced pO2 at rest or exercise-induced) • if possible, BAL and/or lung biopsy performed to exclude infection and malignancy Patient with gut involvement (enteropathy): • typical bowel-related symptoms such as recurrent diarrhoea, malabsorption, weight loss AND/OR • calprotectin in stool = 50µg/g AND • exclusion of infections by stool testing • in case of positive stool testing on current infection, eradication therapy has to be performed before inclusion to trial. Patients with chronic therapy resistant bowel infections can be included. • if possible, inflammation proven with deep bowel biopsy Patients with cytopenias: • platelets = 100.000/µl AND/OR • Hb = 10 g/dl Patients with CNS involvement: • any cerebral lesions in cMRI or cCT • if possible, CSF analysis performed to exclude infection and malignancy Patients with lymphoproliferation: • spleen maximum cephalocaudal diameter = 11 cm AND/OR • enlargement of one lymph node group Patients with involvement of immune system: • HLA-DR+ in CD4+ = 20% AND/OR • CD4+PD1+ = 25% AND/OR • naive B cells (IgM+, IgD+, CD27-) =65 years) yes F.1.3.1 Number of subjects for this age range 5
Exclusion criteria
Exclusion criteria: 1. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial. 2. Other current immunosuppressive treatments with biologicals or DMARDs other than corticosteroids = 20 mg or abatacept. Between treatment with other biologicals or DMARDs and start of abatacept trial treatment the wash out period of the pretreatment must be kept. In case of pretreatment with rituximab, therapy must be stopped at least 6 month before inclusion to trial. 3. Treatment with systemic steroids (prednisolon) in daily dose > 20 mg. 4. Active or chronic Hepatitis B or tuberculosis infection. 5. Active infection or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 30 days prior to baseline. 6. Chronic infection or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 30 days prior to baseline (does not apply for patients already pretreated with abatacept). 7. Acute bacterial or viral infection (patients with a chronic and clinically controlled infection can be included). 8. Patient on antiviral CMV prophylaxis within 28 days prior to baseline visit. 9. Any malignancies within the last 4 years (does not apply for patients already pretreated with abatacept). 10. Current or planned pregnancy, nursing period. 11. EBV load of >5.000 IU/ml or CMV load of > 1.000 IU/ml in plasma at screening. 12. Receipt of a live virus vaccine within 3 months prior to first application of trial medication. 13. Serious uncontrolled concomitant disease not caused by CTLA4 insufficiency or LRBA deficiency. 14. Known HIV infection, infectious hepatitis (type A or C) or another uncontrolled infection. 15. prior HSCT or HSCT planned within next 12 months. 16. Known hypersensitivity to the active substances or any of the excipients. 17. Participation in any other interventional clinical trial within the last 30 days before the start of this trial. 18. Simultaneous participation in other interventional trials; simultaneous participation in registry and diagnostic trials is allowed. 19. Known or persistent abuse of medication, drugs or alcohol. 20. Person who is in a relationship of dependence/employment with the sponsor or the investigator. 21. For women of child bearing potential: Failure to use during treatment with abatacept and at least up to 14 weeks after the last dose of abatacept one of the following safe contraceptive methods that can achieve a failure rate of less than 1 % per year. Such methods include: (1) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), (2) progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), (3) intra-uterine device, (4) intrauterine hormone-releasing system (CTFG recommendations, 2014). This means that women of child bearing potential can only take part in this trial if the risk of becoming pregnant is absolutely minimized. A woman is considered of child bearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy (CTFG recommendations, 2014). Men must agree to use a latex condom during sexual contact with fem
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: to assess the safety of abatacept for patients with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) insufficiency or lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency;Secondary Objective: to assess the efficacy of abatacept for patients with CTLA4 insufficiency or LRBA deficiency;Primary end point(s): Number of episodes of failed infection control under therapy with abatacept during the trial period of one year. An episode of failed infection control is defined as: •a severe infection, defined as: oan infection requiring hospitalization OR oan infection requiring i.v. antibiotic, or i.v. anti-fungal, or i.v. anti-viral treatment OR/AND •the failure to control viral replication. Failure is defined as the occurrence of either EBV viral load = 5.000 IU/ml or CMV viral load = 1.000 IU/ml in plasma in two independent measurements within 2 weeks but at least 7 days apart.;Timepoint(s) of evaluation of this end point: after 12 months treatment within the clinical trial | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety: • Number of severe infections as defined above (i.e. requiring hospitalization, or an infection requiring i.v. antibiotic, i.v. anti-fungal, or i.v. anti-viral treatment). • Characterization (incl. type of pathogen and involved organ system) of severe infections (definition see above) during abatacept trial treatment period. Efficacy: - overall Survival (OS) - event free Survival (EFS) - treatment failure, defined as any premature termination of treatment for any reason - cumulative steroid dose - cumulative dose of concomitant drugs to alleviate symptoms such as diarrhoea medications or pain medication - CGI-I - quality of live measured by SF36 - CHAI-Morbidity Score - laboratory parameters In addition endpoints dependent on the patient’s organ involvement;Timepoint(s) of evaluation of this end point: after 12 months treatment within the clinical trial | — |
Countries
Germany
Contacts
Public ContactCoordinating Investigator
Universitätsklinikum Freiburg
Outcome results
None listed