E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Hemophagocytic Lymphohistiocytosis (pHLH) |
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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 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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071583 |
E.1.2 | Term | Haemophagocytic lymphohistiocytosis |
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 gather additional safety and efficacy data on emapalumab in pHLH patients.
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E.2.2 | Secondary objectives of the trial |
• To assess a starting dose of emapalumab of 3 mg/kg.
• To assess the impact of emapalumab on Quality of Life (QOL).
• To gather additional evidence on the long-term outcome of pHLH patients treated with emapalumab.
• To further evaluate the pharmacokinetic (PK) profile of emapalumab in pHLH patients.
• To further evaluate the pharmacodynamic (PD) effects (levels of circulating Total Interferon Gamma (IFNγ) and biomarkers of its neutralization, namely CXCL9 and CXCL10).
• To assess the profile of other relevant HLH biomarkers, e.g., sCD25 and other exploratory biomarkers.
•To monitor for potential occurrence of anti-drug antibodies (ADAs). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Of note, the enrolment of patients will continue until emapalumab is commercially available for a given indication, or until sample size is reached, whichever comes first; thus, US enrolment will be limited to treatment-naïve patientsю Male and female pHLH patients, from birth up to and including 18 years at diagnosis of HLH.
2. A molecular diagnosis or familial history consistent with pHLH or fulfilment of HLH-2004 diagnostic criteria, i.e., five of the eight criteria below:
- 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.
3. Presence of active HLH disease as assessed by the treating physician.
4. Patients having already received conventional HLH therapy must fulfil one of the following criteria as assessed by the treating physician:
- Having not responded
- Having not achieved a satisfactory response
- Having reactivated
- Showing intolerance to previous conventional treatment of HLH.
5. Informed consent signed by the patient (as required by local law), or by the patient’s legally authorized representative(s) with the assent of patients who are legally capable of providing it, as applicable.
6. Having received guidance on contraception for both male and female patients sexually active and having reached puberty.
Females of child-bearing potential require use of highly effective contraceptive measures (failure rate of less than 1% per year) 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 (such as sexual abstinence, barrier contraception, vasectomy) to avoid fathering a child from Screening until 6 months after receiving last dose of study drug.
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E.4 | Principal exclusion criteria |
1. Diagnosis of secondary HLH consequent to a proven rheumatic, metabolic or neoplastic disease.
2. Active mycobacteria, Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter or Leishmania infections.
3. Evidence of latent tuberculosis.
4. Presence of malignancy.
5. Patients who have another concomitant disease or malformation severely affecting cardiovascular, pulmonary, central nervous system (CNS), liver, or renal function that in the opinion of the Investigator may significantly affect the likelihood to respond to treatment and/or the assessment of emapalumab safety and/or efficacy.
6. History of hypersensitivity or allergy to any component of the study regimen (e.g., polysorbate).
7. Receipt of a bacille Calmette-Guerin (BCG) vaccine within 12 weeks prior to Screening.
8. Receipt of a live or attenuated live (other than BCG) vaccine within 6 weeks prior to Screening.
9. 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, i.e., achievement of either Complete or Partial Response or HLH Improvement, at End of Treatment (EOT) or Week 8 (whichever occurs earlier).
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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:
• Overall Survival, including survival to HSCT and survival after either HSCT or last emapalumab infusion (if HSCT is not performed)
• Event-free Survival
• Overall Response, i.e., achievement of either Complete or Partial Response or HLH Improvement, at start of conditioning (or at last emapalumab infusion if HSCT is not performed)
• Duration of Response, ie, maintenance of response achieved any time during the study (with censoring time at start of conditioning for patients with no events)
• Time to Response at any time during the study
• Number of patients able to reduce glucocorticoids by 50% or more of baseline dose during emapalumab treatment
• Number of patients able to proceed to HSCT, when deemed indicated
• QOL indices.
Safety endpoints:
• Incidence, severity, causality and outcomes of AEs (serious and non-serious).
• Evolutions of relevant laboratory parameters, e.g., complete blood cell (CBC) count, liver and renal function tests, and coagulation parameters.
• Number of patients who discontinued emapalumab treatment for safety reasons.
PK/PD Endpoints:
• Serum concentrations of emapalumab to further evaluate emapalumab PK profile.
• Determination of PD parameters (levels of circulating total IFNγ and markers of its neutralization, namely CXCL9 and CXCL10).
• Determination of other relevant disease biomarkers, eg, sCD25 and other exploratory biomarkers.
• Measurement of emapalumab concentrations and PD parameters in other matrices, eg, cerebrospinal fluid (CSF), bronchoalveolar lavage fluid (BALF), if clinically appropriate (exploratory).
• Level (if any) of circulating antibodies against emapalumab (ADAs).
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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) | 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 | 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 | 15 |
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 |
France |
Germany |
Italy |
Spain |
Sweden |
Switzerland |
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 | 2 |
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 | 4 |