A Study for Long-term Follow-up of Hemophagocytic Lymphohistiocytosis (HLH) Participants Who Received Treatment With Emapalumab (NI-0501), an Anti-interferon Gamma Monoclonal Antibody

Study Overview
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Brief Summary
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International, multicenter, long-term, follow-up study that will enrol HLH participants who have received emapalumab in previous clinical trials, in the context of the clinical development program for emapalumab or under compassionate use (CU).

Detailed Description
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The aim of this study is to monitor the long-term safety profile of emapalumab in participants who have previously received at least one dose of emapalumab, including survival time after the administration of emapalumab. Moreover, the elimination profile of emapalumab and the immunogenicity will also be assessed. Furthermore, safety, tolerability, efficacy, and pharmacokinetic (PK) profile of emapalumab will be closely monitored in the event that some participants, upon request of the treating physician, will receive emapalumab treatment in the follow-up study.

Official Title
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A Multicenter Study for the Long-term Follow-up of HLH Patients Who Received Treatment With NI-0501, an Anti-interferon Gamma Monoclonal Antibody

Conditions
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Hemophagocytic Lymphohistiocytosis

Intervention / Treatment
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* Drug: Emapalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Having received at least one dose of emapalumab. Having signed the Informed Consent by the participant or the participant's legal representative(s), as applicable, with the assent of participant who are legally capable of providing it. Exclusion Criteria: None
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Enrolled-04 Cohort<br>Participants enrolled in Study NI-0501-04 (NCT01818492) will be invited to participate for long-term follow-up for 1 year either after haematopoietic stem cell transplantation (HSCT) or after the last administration of emapalumab. In Study NI-0501-04, participants received emapalumab for 4 to 8 weeks. After the treatment period, participants could have undergone HSCT. Participants for whom an appropriate donor was not identified by Week 8, or in a case where HSCT will be delayed for reasons unrelated to the administration of emapalumab, can continue receiving treatment with emapalumab beyond the foreseen 8 weeks in the current study (NI-0501-05, NCT02069899) at the request of the investigator, providing a favorable benefit/risk assessment of treatment is established. The dose and timing was either carried forward from the last administered emapalumab dose as part of the parent protocol or an adjusted dose was administered, if necessary. | Drug: Emapalumab<br>* Treatment with emapalumab is not planned for all enrolled participants. For participants who will continue receiving emapalumab in the context of this study (NI-0501-05), the dose and timing will be either carried forward from the last administered emapalumab dose as part of the parent study in which the participant was enrolled, or an adjusted dose will be administered, if necessary.<br>* Other names: NI-0501;|
| No Intervention: Enrolled-06 Cohort<br>All participants who received at least 1 dose of emapalumab and were monitored for at least 4 weeks after the last drug administration in Study NI-0501-06 (NCT03311854) will be invited to participate for long-term follow-up for 1 year after the last administration of emapalumab. Participants will not receive emapalumab in the current study (NI-0501-05, NCT02069899). | |
| Other: Enrolled-CU Cohort<br>In exceptional cases, at the spontaneous request of a treating physician, CU treatment will be granted to the participants who had exhausted all possible treatment options and who could not be enrolled in a clinical study. All participants who receive at least 1 dose of emapalumab under CU will be invited to participate for long-term follow-up for 1 year either after HSCT or after the last administration of emapalumab. Participants can continue treatment in the context of the current Study (NI-0501-05, NCT02069899) while stem cell donor search is ongoing, or if the investigator assesses that continuation of treatment is beneficial. | Drug: Emapalumab<br>* Treatment with emapalumab is not planned for all enrolled participants. For participants who will continue receiving emapalumab in the context of this study (NI-0501-05), the dose and timing will be either carried forward from the last administered emapalumab dose as part of the parent study in which the participant was enrolled, or an adjusted dose will be administered, if necessary.<br>* Other names: NI-0501;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Event (AE) | Adverse events were defined as any undesirable experience occurring in a participant during the study, whether or not considered related to emapalumab. | From the date of enrollment in this study up to 1 year either after HSCT or after the last administration of emapalumab (maximum duration: 639 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Duration of Response (Enrolled-04 Cohort) | Cumulative duration of response: total number of days in response from 1st achievement of overall response until HSCT or last treatment date if the participant did not undergo HSCT. Overall response: achievement of either Complete (CR) or Partial Response (PR), or HLH Improvement (HI). CR: no fever, normal spleen size, no cytopenia (absolute neutrophil count [ANC] ≥1.0 x 10^9/L and platelet count ≥ 100 x 10^9/L), no hyperferritinemia (serum ferritin <2000 μg/L), no coagulopathy (normal D-dimer and/or fibrinogen >150 mg/dL), no neurological and cerebrospinal fluid [CSF] abnormalities attributed to HLH, no sustained worsening of soluble cluster of differentiation (CD) 25. PR: at least 3 HLH clinical and laboratory criteria (including central nervous system [CNS] abnormalities) met the CR criteria, no progression of other aspects of HLH disease pathology. HI: improvement (>50% change from baseline) of at least 3 HLH clinical and laboratory abnormalities (including CNS involvement). | From 1st achievement of overall response until HSCT or last treatment date if participant did not undergo HSCT (maximum 250 days) | 
| Duration of First Response (Enrolled-06 Cohort) | Duration of first response was defined as the number of days between first date of response and first date of loss of response or death. Response was defined as macrophage activation syndrome (MAS) remission, which was resolution of clinical signs and symptoms according to the Investigator (MAS clinical signs and symptoms score ≤ 1) and normalization of laboratory parameters relevant to MAS as follows: white blood cells (WBC) and platelet count above the upper limit of normal (LLN), Lactate dehydrogenase < 1.5 × lower limit of normal (ULN), aspartate aminotransferase/alanine aminotransferase <1.5 × ULN, fibrinogen > 100 mg/dL, ferritin level decreased by at least 80% from values at screening or baseline (whichever was higher) or < 2000 ng/mL, whichever was lower. | From first date of response and first date of loss of response or death (maximum 416 days) | 
| Overall Survival (Enrolled-04 Cohort) | Overall survival was defined as time from the date of the last emapalumab dose to the date of death. Participants without an event were censored at the time of last contact or 12 months after last dose (whichever came first). As some participants had their last emapalumab dose in the parent study (NI-0501-04), data from both NI-0501-05 and NI-0501-04 studies were considered for the assessment of overall survival. Kaplan-Meier methodology was used for estimation. | From the date of last of emapalumab dose to the date of death or last contact or 12 months after last dose, whichever came first (maximum 366 days) | 
| Overall Survival (Enrolled-06 Cohort) | Overall survival was defined as time from the date of last emapalumab dose to the date of death. Participants without an event were censored at the time of last contact or 12 months after last dose (whichever came first). As participants in the Enrolled-06 Cohort did not receive emapalumab in the current study, data from both NI-0501-05 and NI-0501-06 studies were considered for the assessment of overall survival. Kaplan-Meier methodology was used for estimation. | From the date of last of emapalumab dose to the date of death or last contact or 12 months after last dose, whichever came first (maximum 366 days) | 
| Percentage of Participants Who Achieved Engraftment (Enrolled-04 Cohort) | For participants who underwent HSCT either in parent study (NI-0501-04) or current study (NI-0501-05), engraftment rate was based on the number of participants experiencing primary or secondary graft failure (blood stem cell transplant failure, engraft failure, or transplant dysfunction), as reported as an adverse event. | From HSCT up to 12 months | 
| Percentage of Participants Who Achieved Donor Chimerism (Enrolled-04 Cohort) | For participants who underwent HSCT, achievement of donor chimerism was considered based on donor chimerism in peripheral blood completed, that is, donor cells >95%. | From HSCT to 12 months | 
| Percentage of Participants With Graft-versus-host-disease (Enrolled-04 Cohort) | Occurrence of graft-versus-host-disease, reported in Study NI-0501-05 as an AE. | From HSCT to 12 months | 
| MAS Activity Level as Assessed by Visual Analogue Scale (Enrolled-06 Cohort) | MAS activity was monitored using a visual analogue scale ranging from 0 to 10 with a higher score indicted higher disease activity. | Baseline (first NI-0501-05 visit), Day 100, Month 12/End of Study | 
| Circulating Emapalumab Level (Enrolled-04 Cohort) | Circulating Emapalumab level in Enrolled-04 Cohort who continued to receive treatment with emapalumab in the current study (NI-0501-05). | First infusion day (infusion duration: 1-2 hours) in Study NI-0501-05, last infusion day (infusion Day 188), 12 months post-transplant | 
| Circulating Emapalumab Level (Enrolled-06 Cohort) |  | Baseline (first NI-0501-05 visit), Day 100, Month 6 | 
| Total Human Interferon Gamma Levels (Enrolled-04 Cohort) |  | First infusion day (infusion duration: 1-2 hours) in Study NI-0501-05, Day 100 post-transplant, 12 months post-transplant | 
| Total Human Interferon Gamma Levels (Enrolled-06 Cohort) |  | Baseline (first NI-0501-05 visit), Day 100, Month 12/End of Study | 
| Number of Participants With Anti-drug Antibody |  | From enrolment up to 12 months post-transplant or last emapalumab infusion (maximum 639 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophagocytic lymphohistiocytosis (HLH) previously treated with NI-0501, Emapalumab