E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary haemophagocytic lymphohistiocytosis which has reactivated or an unsatisfactory response has been achieved. |
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E.1.1.1 | Medical condition in easily understood language |
A rare, life-threatening condition affecting predominantly children. The disease is characterized by uncontrolled hyper-inflammation on the basis of underlying immune deficiencies. |
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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 | 17.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10010331 |
E.1.2 | Term | Congenital, familial and genetic disorders |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 determine the preliminary safety and tolerability profile of multiple IV administrations of NI-0501 • To determine a preliminary efficacy and benefit/risk profile of NI-0501 in HLH patients • To describe the pharmacokinetic (PK) profile of NI-0501 in HLH patients • To define an appropriate NI-0501 therapeutic dose regimen for HLH • 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, who have been previously treated by conventional induction therapy 2. Patients must also, a. Present Reactivation, or Worsening, or No Further Improvement of the disease (for at least 4 weeks from initiation of treatment) after having achieved at least Partial or Incomplete Response OR b. Show No Response for at least 2 weeks from initiation of treatment or Worsening of the disease OR c. Show Intolerance to conventional treatment of HLH, as judged by the treating physician 3. Diagnosis of primary HLH according to the following criteria (as per the HLH-2004 protocol): a. A molecular diagnosis or familial history consistent with primary HLH OR b. Five out of the eight criteria below are fulfilled: - Fever - Splenomegaly - Cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin < 90 g/L; platelets < 100 x 109/L; neutrophils < 1 x 109/L) - Hypertriglyceridemia (fasting triglycerides ≥ 3 mmol/L or ≥ 265 mg/dL) and/or hypofibrinogenemia (≤ 1.5 g/L) - Hemophagocytosis in bone marrow, spleen or lymph nodes, with no evidence of malignancy - Low or absent natural killer (NK)-cell activity - Ferritin ≥ 500 µg/L - Soluble CD25 (sCD25; i.e. soluble IL-2 receptor) ≥ 2400 U/mL. In case the diagnosis of HLH is based on the 5 of the 8 above criteria (and not on a molecular finding or a familial history consistent with primary HLH), the patient is eligible to enter the study if there is a. Reactivation, or Worsening, or No Further Improvement (for at least 4 weeks from initiation of treatment) of the disease after having achieved at least Partial or Incomplete Response. In this specific situation, Worsening and No Further Improvement must include abnormal sCD25 or ferritin > 2000 ng/ml OR b. No Response (for at least 2 weeks from initiation of treatment) or Worsening of the disease (without previous Partial or Incomplete Response). Soluble CD25 must be abnormal or ferritin > 2000 ng/ml and the evaluation and approval by the Scientific Steering Committee is mandatory (see definitions in Table 1) OR c. Intolerance to conventional treatment of HLH, as judged by the treating physician and approval by the Scientific Steering Committee is mandatory 4. Patients must have received treatment for HLH according to the conventional therapy at the site (e.g. corticosteroids alone or in combination with etoposide, CsA, methotrexate etc.). At the time of enrollment, eligible patients might still be receiving treatment (induction or maintenance) or might have already discontinued it. 5. Informed consent signed by the patient (if ≥ 18 years old), or by the patient’s legal representative(s) with the assent of patients who are legally capable of providing it. 6. 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 partners(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 • anti-CD20, as part of EBV infection treatment, within the previous week prior to screening • any other biologic drug within 5 times their defined half-life period (a list of some of the most commonly used biologic half-lives will be included in the Study Specific Risk Management Plan) 4. Isolated or multiple acute organ failure(s) (heart, lung or kidney), requiring aggressive therapy such as high doses of inotropic drugs, circulatory assistance, hemofiltration or haemodialysis, artificial ventilation. 5. Active mycobacteria, Shigella, Campylobacter, Leishmania or Salmonella infections. 6. Evidence of past or active tuberculosis. 7. Positive serology for HIV antibodies, hepatitis B surface antigen or hepatitis C antibodies. 8. History of malignancy. 9. Patients who have another concomitant disease or malformation severely affecting cardiovascular, pulmonary, liver or renal function. 10. History of hypersensitivity or allergy to any component of the study regimen. 11. Vaccination with a live or attenuated live (including BCG) vaccine within the previous 12 weeks prior to screening. 12. Pregnant or lactating female patients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• 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 - 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 - Number of patients withdrawn for safety issues • Evolution of clinical signs (fever, splenomegaly, CNS symptoms) and laboratory parameters (CBC, fibrinogen, serum triglycerides, ferritin, soluble CD-25 levels), which characterize the disease, will be used to assess response and time to response. As this is a pilot study, all endpoints will be considered exploratory. - Number of patients showing partial or complete response by week 2, 4 or 8 - Number of patients achieving non-active disease by week 8 - Time to achievement of non-active disease state - Time to achievement of complete response - Time to achievement of partial response - Time to reactivation - Survival at week 8 and at the end of the follow-up period (week 12) - Number of patients achieving no response at any time - Number of patients showing reactivation at any time.
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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) |
• Other parameters: - Blood concentration of NI-0501 to determine NI-0501 pharmacokinetics in patients - Determination of pharmacodynamic effects (levels of circulating IFNγ and of any other potential markers of disease activity or predictors of response) - Level (if any) of circulating antibodies against NI-0501 to determine immunogenicity (ADA). |
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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) | 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
| Yes |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Austria |
Czech Republic |
Germany |
Italy |
Spain |
Turkey |
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 | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |