E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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 |
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E.1.1.1 | Medical condition in easily understood language |
medical condition is molecular defined as CTLA4 insufficiency, i.e. less production of protein CTLA4 or LRBA deficiency, i.e. less production of LRBA |
Die Erkrankung ist molekular definiert als CTLA4-Insuffizienz bzw. LRBA-Defizienz. D. h. entweder wird das Protein CTLA4 oderdas Protein LRBA nicht ausreichend produziert. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10021449 |
E.1.2 | Term | Immunodeficiency common variable |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
to assess the efficacy of abatacept for patients with CTLA4 insufficiency or LRBA deficiency |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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-) < 55%
Patients with skin involvement: • skin lesions on body surface • eczematous, ulcerative or psoriasis-like skin lesions |
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E.4 | Principal 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 females of child bearing potential while participating in this trial even if he has undergone a successful vasectomy. Patients must abstain from donating semen or sperm during participation in the trial. All patients must abstain from donating blood.
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E.5 End points |
E.5.1 | 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: o an infection requiring hospitalization OR o an 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 12 months treatment within the clinical trial |
nach der 12monatigen Behandlung in der klinischen Prüfung |
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E.5.2 | 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
after 12 months treatment within the clinical trial |
nach der 12monatigen Behandlung in der klinischen Prüfung |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 33 |
E.8.9.1 | In the Member State concerned days | |