E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NLRC4 mutation XIAP deficiency |
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E.1.1.1 | Medical condition in easily understood language |
NLRC4 mutation XIAP deficiency |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
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 clinical efficacy of Tadekinig alfa in monogenic autoinflammatory diseases with ongoing inflammation and deleterious mutations of NLRC4-MAS or XIAP - To assess laboratory/biological evidence of efficacy
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E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objective: - Main clinical features and laboratory biomarkers (characteristics of each patient profile) will be assessed longitudinally during the SAOL phase for each experimental subject Secondary Safety Objective: - To assess the safety and tolerability of Tadekinig alfa treatment in monogenic, autoinflammatory disease harboring deleterious mutations of NLRC4-MAS or XIAP
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation). If possible, flow cytometry assay will be performed in parallel to confirm diagnosis of XIAP deficiency. (Note: Previous flow cytometry assay results will be permitted for confirmation of XIAP deficiency diagnosis.) A genetic diagnosis from a local laboratory will be accepted for enrolment and start of treatment, to avoid any treatment delays for these severe conditions. However, the genetic diagnosis has to be confirmed by the central laboratory. If the genetic diagnosis is not confirmed, the patient will discontinue the study. - Patients with XIAP deficiency and a previous bone marrow transplantation are allowed, if they show evidence of primary or secondary graft failure, or failure to achieve phenotypic correction with evidence of XIAP-related disease recurrence or clinically significant mixed chimerism. For these patients, genetic diagnosis at the central laboratory may show chimerism; thus, local genetic diagnosis prior to the bone marrow transplantation will be the main source to confirm the genetic diagnosis. - Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥4 - Patients receiving corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying anti rheumatic drugs (DMARDs), and/or IL-1 blockade with insufficient response to treatment upon enrollment are allowed into the study. Patients not receiving any of these treatments before start of therapy are also allowed - Women of childbearing potential with negative urine pregnancy test (UPT) at all visits |
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E.4 | Principal exclusion criteria |
- Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency - Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology) - Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy - Presence of life threatening infections - Oncologic causes of symptoms; current or previous history of malignancy - Presence of CNS manifestations - Patients suffering from familial hemophagocytic lymphohistiocytosis (f HLH) - Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods - Concomitant use of immunosuppression therapies excluded by the protocol. - Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent - Hypersensitivity to the active substance or one of the excipients of the investigational product |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is the time to first occurrence of disease reactivation (including full and partial disease reactivation) during the 16-week RW phase. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
16 weeks or occurence of first disease reactivation |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint
Response to therapy (including complete response and partial response) in the SAOL phase from Week 10 onwards and observed at least at 2 consecutive visits at least 2 weeks apart during the SAOL phase
Other Secondary Efficacy Endpoints
- Best response to therapy during the SAOL phase (including complete response and partial response and disease improvement) - Duration of response to therapy (including complete response and partial response) during the SAOL phase - Disease reactivation rate for individual subjects (number of disease reactivations experienced per week while each subject is on the study treatment during the SAOL phase) - Treatment failures (i.e. patients who experience at least one disease reactivation) - Intensity of disease reactivations (defined by the level of activity given by the mAIDAI – both objective and subjective criteria) - Serum CRP, Serum Ferritin - Improvement of fevers, improvement of hepato/splenomegaly (clinical assessments if present at Baseline) - Improvement in serum albumin and liver transaminases, anemia and/or platelet count (if present at Baseline) - Hospital length of stay - Length of hospitalisation - Physician Global Assessment - Patient’s or caregiver’s qualitative evaluation of health status - Presence of skin rash - evolution if present at Baseline or appearance during the study - Tolerance to oral/enteral nutrition for hospitalized patients if intestinal dysfunction was present at Baseline - Improvement of stool output for hospitalized patients if intestinal dysfunction was present at Baseline
Safety and Tolerability Endpoints
- Adverse events will be reported - Physical examination findings and vital signs: clinically significant changes from Baseline - Laboratory assessments including clinically significant changes from Baseline in hematology with platelet counts, CRP, ESR, ferritin, fibrinogen, D-dimer, liver enzymes, creatinine and glomerular filtration rate. (All clinically significant abnormal laboratory results or assessments must be followed until they resolve (return to normal or Baseline values) or stabilize, or until they are judged by the Investigator to be no longer clinically significant) - Immunogenicity evaluation: Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies - Local tolerability at the injection site |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Genetic testing at screening : analysis to detect known detrimental gene mutations |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
United States |
Germany |
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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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The end of the entire trial will be defined as the date of the final clinical database lock |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |