E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Haemophagocytic lymphohistiocytosis |
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E.1.1.1 | Medical condition in easily understood language |
A rare, life-threatending condition affecting predominantly children. The disease is characterized by uncontrolled inflammation. |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071583 |
E.1.2 | Term | Haemophagocytic lymphohistiocytosis |
E.1.2 | System Organ Class | 100000004851 |
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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 determine the safety and tolerability profile of multiple IV administrations of NI-0501 • To determine the efficacy and benefit/risk profile of NI-0501 in HLH patients • To describe the pharmacokinetic (PK) profile of NI-0501 in HLH patients • To determine the PD effects (levels of circulating Total IFNγ and biomarkers of its neutralization, namely CXCL9 and CXCL10) • To define an appropriate NI-0501 therapeutic dose regimen for HLH • To determine other biomarkers, e.g. sCD25, IL-10 • To assess the immunogenicity of NI-0501 |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Primary HLH patients of both genders, up to and including 18 years at diagnosis of HLH, or at an age appropriate to be treated in the investigator's practice. The diagnosis must be made on the following criteria (as per HLH-2004 protocol): a. A molecular diagnosis or familial history consistent with primary HLH OR b. 5 out of 8 criteria below are fulfilled: - Fever - Splenomegaly - Cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin <90g/L; platelets <100x10^9/L; neutrophils <1x10^9/L) - Hypertriglyceridemia (fasting triglycerides >3mmol/L or >265mg/dL) and/or hypofibrinogenemia (≤1.5g/L) - Hemophagocytosis in bone marrow, spleen or lymph nodes, with no evidence of malignancy - Low or absent natural killer (NK)-cell activity - Ferritin ≥500μg/L - Soluble CD25 (sCD25; i.e. soluble IL-2 receptor) ≥2400U/mL 2. Presence of active disease as assessed by treating physician 3. Patients having already received HLH conventional therapy must fulfill one of the following criteria as assessed by the treating physician: - Having not responded - Having not achieved a satisfactory response - Having not maintained a satisfactory response - Showing intolerance of conventional HLH treatment At the time of enrollment, eligible patients might still be receiving treatment (induction or maintenance) or might have discontinued it. 4. Informed consent signed by the patient (if ≥18 years old) or by their legally authorized representative(s) with the assent of patients who are legally capable of providing it. 5. Having received guidance on contraception for both male and female patients sexually active and having reached puberty: Females of child-bearing potential, having a negative pregnancy test at screening and unless true abstinence is in line with the preferred and usual lifestyle of the patient, must agree to use adequate method(s) of birth control from screening until 6 months after receiving last dose of the study drug. Males with partner(s) of child-bearing potential must agree to take appropriate precautions to avoid fathering a child from screening until 6 months after receiving last dose of the study drug. |
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E.4 | Principal exclusion criteria |
1. Diagnosis of secondary HLH consequent to a proven rheumatic or neoplastic disease. 2. Body weight < 3 kg. 3. Patients treated with: - any T-cell depleting agents (such as anti-thymocyte globulin [ATG], anti-CD52) during the previous 2 weeks prior to screening - any other biologic drug within 5 times their defined half-life period, expect for rituximab in case of documented B-cell EBV infection 4. Active mycobacteria, Histoplasma Capsulatum, Shigella, Campylobacter, Leishmania or Salmonella infections. 5. Evidence of history of tuberculosis or latent tuberculosis. 6. Positive serology for HIV antibodies, hepatitis B surface antigen or hepatitis C antibodies. 7. Presence of malignancy. 8. Patient who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, liver or renal function. 9. History of hypersensitivity or allergy to any components of the study regimen. 10. Receipt of a live or attenuated live (including BCG) vaccine within the last 12 weeks before screening. 11. Pregnant or lactating female patients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Primary efficacy endpoint: - Overall response Rate, i.e. achievment of either Complete or Partial response of HLH Improvement at End of Trial (EoT) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Secondary efficacy endpoints: - Time to Response any time during the study - Durability of Response, i.e. maintenance of response achieved any time during the study until EoT and beyond (including data collected in the long-term follow-up study NI-0501-05) - Number of patients who reduce glucocorticoids by 50% or more of the baseline dose - Number of patients able to proceed to HSCT, when deemed indicated - Survival at Week 8 (or EoT) and at the end of the study • Other parameters: - Blood concentration of NI-0501 to determine NI-0501 pharmacokinetics in patients (TP1 - each visit, TP2 - end of treatment visit) - Determination of pharmacodynamic effects (levels of circulating IFNγ, markers of INFγ and other biomarkers (TP1 - each visit, TP2 - end of treatment visit) • Safety and tolerability of multiple IV infusions of NI-0501 will be assessed as follows: - Incidence, severity, causality and outcomes of Adverse Events (serious and non-serious), with particular attention being paid to infections - Evolution of laboratory parameters such as complete blood cell count (CBC), with a focus on red cells (haemoglobin), neutrophils and platelets, liver tests, renal function tests and coagulation (Treatment period (TP) 1 - mandatory on Days 3 and 6, TP2 every 6-7 days) - Number of patients withdrawn for safety issues - Level (if any) of circulating antibodies against NI-0501 to determine immunogenicity; i.e. the development of anti-drug antibodies (ASAs) (TP2 - End of treatment visit) • Safety parameters to be collected and assessed: - Incidence, severity, causality and outcomes of Adverse Events (serious and non-serious), with particular attention being paid to infections |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 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) | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Germany |
Italy |
Spain |
Sweden |
Turkey |
United Kingdom |
United States |
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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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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |