Trial document




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  DRKS00017736

Trial Description

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Title

Safety and Efficacy of abatacept (s.c.) in patients with CTLA4 insufficiency or LRBA deficiency

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Trial Acronym

ABACHAI

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URL of the Trial

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Brief Summary in Lay Language

This clinical trial will evaluate the safety and efficacy of the drug Abatacept (trade name: Orencia®) in patients with CTLA4 insufficiency or LRBA deficiency. In CTLA4 insufficiency, a mutation causes the CTLA4 molecule to lose its inhibitory effect on pro-inflammatory and autoimmune cells of the immune system. The resulting malfunctioning of the immune system can trigger an autoimmune organ disease, whereby the symptoms can vary from patient to patient. They range from recurrent, increased infections of the respiratory tract, possibly with pneumonia, to gastrointestinal complaints and neurological impairments. Genetic mutations in the LRBA gene lead to a secondary loss of CTLA4 and thus to the same effects as a CTLA4 mutation itself.
The drug Abatacept is a soluble fusion protein that can replace the inhibitory effect of CTLA4 and thus counteract the overactivated immune system.
In the study, 20 patients will be treated with Abatacept for 12 months, with patients injecting the drug under the skin themselves on a weekly basis. The study will focus on the potential side effects of Abatacept. Data on efficacy will also be collected. In addition to the analysis of clinical data and laboratory values, the study is also investigating how treatment with Abatacept affects the patients quality of life. This will enable ABACHAI to make patient-relevant statements on a possible new treatment option for these rare diseases.

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Brief Summary in Scientific Language

Patients with genetic defects in CTLA4 have been shown to have a reduced CTLA4 expression, patients with LRBA deficiency show an increased turnover of the CTLA4 molecule, both mutations are leading to a similar clinical phenotype. CTLA4 plays an important role in the maintenance of immune homeostasis and patients with CTLA4 defect present with features of severe immune dysregulation. The rationale of this clinical trial is therefore to substitute the deficient CTLA4 by administration of CTLA4-Ig (abatacept) as a form of causative treatment.

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Do you plan to share individual participant data with other researchers?

No

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00017736
  •   2020/07/06
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  •   yes
  •   Approved
  •   42/20 (FF-MC), Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  •   2019-000972-40 
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Health Condition or Problem studied

  •   CTLA4 insufficiency or LRBA deficiency
  •   D84.9 -  Immunodeficiency, unspecified
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Interventions/Observational Groups

  •   125 mg abatacept s.c. once weekly during a period of 12 months
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   IIa
  •   Yes
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Primary Outcome

Number of episodes of failed infection control under therapy with abatacept during the trial period of one year.

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Secondary Outcome

- Number of severe infections (i.e. hospitalisation required, or an infection requiring i.v. antibiotic, i.v. antifungal or i.v. antiviral treatment)
- Characterization (including pathogen type and affected organ system) of severe infections during study treatment with Abatacept.
- overall survival
- event-free survival
- treatment failure, defined as premature discontinuation of study treatment for any reason
- cumulative steroid dose
- cumulative dose of concomitant drugs to alleviate symptoms, such as diarrhoea or pain medication
- Clinical Global Impression – Improvement Skala (CGI-I)
- quality of life measured by SF 36
- CHAI-Morbidity Score
- laboratory parameters

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2020/07/21
  •   20
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional 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, Patient with gut involvement (enteropathy), Patients with cytopenias, Patients with CNS involvement, Patients with lymphoproliferation, Patients with involvement of immune system, Patients with skin involvement,

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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 3 month before inclusion to trial.
3. Treatment with systemic steroids (prednisolon) in daily dose > 20 mg.
4. Active Hepatitis B or tuberculosis infection.
5. Chronic or active infection or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 30 days prior to baseline.
6. Acute bacterial or viral infection (patients with a chronic and clinically controlled infection can be included).
7. Patient on antiviral CMV prophylaxis
8. Any malignancies within the last 4 years.
9. Current or planned pregnancy, nursing period.
10. EBV load of >5.000 IU/ml or CMV load of > 1.000 IU/ml in plasma at screening.
11. Receipt of a live virus vaccine within 3 month prior to first application of trial medication.
12. Serious uncontrolled concomitant disease not caused by CTLA4 insufficiency or LRBA deficiency.
13. Known HIV infection, infectious hepatitis (type A or C) or another uncontrolled infection.
14. prior HSCT or HSCT planned within next 12 months.
15. Known hypersensitivity to the active substances or any of the excipients.
16. Participation in any other interventional clinical trial within the last 30 days before the start of this trial.
17. Simultaneous participation in other interventional trials; simultaneous participation in registry and diagnostic trials is allowed.
18. Known or persistent abuse of medication, drugs or alcohol.
19. Person who is in a relationship of dependence/employment with the sponsor or the investigator.
20. 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).

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Addresses

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    • Universitätsklinikum Freiburg vertreten durch den Leitenden Ärztlichen Direktor und die Kaufmännische Direktion
    • Breisacher Straße 153
    • 70110  Freiburg
    • Germany
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    • Universitätsklinikum Freiburg Klinik für Rheumatologie und Klinische Immunologie und Institut für Chronische Immundefizienz (CCI)
    • Mr.  Prof. Dr.  Bodo  Grimbacher 
    • Breisacher Str. 115
    • 79106  Freiburg
    • Germany
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    • Universitätsklinikum Freiburg Klinik für Rheumatologie und Klinische Immunologie und Institut für Chronische Immundefizienz (CCI)
    • Mr.  Prof. Dr.  Bodo  Grimbacher 
    • Breisacher Straße 115
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung (BMBF)
    • Heinemannstraße 2
    • 53175  Bonn
    • Germany
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    • Bristol-Myers Squibb GmbH & Co. KGaA
    • Arnulfstraße 29
    • 80636   München
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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