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

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

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).

Study Overview

• Status: Completed
• Conditions: Hemophagocytic Lymphohistiocytosis
• Intervention / Treatment: Drug: Emapalumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75743
    • Hopital Necker-Enfants Malades
• Italy
  • Monza, Italy, 20900
    • Fondazione MBBM c/o Ospedale San Gerardo Clinica Pediatrica
  • Padova, Italy, 35128
    • Azienda Ospedaliera Padova
  • Rome, Italy, 00165
    • Ospedale Pediatrico Bambino Gesù
  • Rome, Italy, 00165
    • Ospedale Pediatrico Bambino Gesu - UO Reumatologia
  • Verona, Italy, 37126
    • Ospedale della Donna e del Bambino - U.O.C. Oncoematologia Pediatrica
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron Servei de Hematologia i Oncologia
  • Barcelona, Spain, 08950
    • Sant Joan de Déu Hospital - Pediatric Rheumatology Department
  • Madrid, Spain, 28009
    • Hospital Universitario Niño Jesús Servicio de Hemato-Oncología Pediátrica
• United Kingdom
  • London, United Kingdom, WC1N1EH
    • UCL Institute of Child Health Great Ormond Street Hospital
  • London, United Kingdom, WC1N3JH
    • Great Ormond Street Hospital - Department of Haematology
• United States
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Helen Devos Children's Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina At Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital - Division of Immunobiology
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Enrolled-04 Cohort; 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; 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.; Other Names: NI-0501
No Intervention: Enrolled-06 Cohort; 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; 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; 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.; Other Names: NI-0501

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Swedish Orphan Biovitrum
• Collaborators: Seventh Framework Programme

Publications and helpful links

General Publications

• Jordan MB, Locatelli F, Allen C, Cesaro S, Rizzari C, Rao A, Degar B, Garrington T, Sevilla J, Putti MC, Fagioli F, Ahlmann M, Dapena Diaz JL, Henry M, Grom A, De Benedetti F, de Min C. Post-Transplant Outcomes of Children with Primary Hemophagocytic Lymphohistiocytosis Treated with Emapalumab.Transplant Cell Ther. 2021; 27(Supplement 3): S118.
• Laveille C, Jacqmin P, de Graaf K, de Min C. Population Pharmacokinetic Analysis of Emapalumab, a Fully Human, Anti-Interferon Gamma Monoclonal Antibody, in Children with Primary Hemophagocytic Lymphohistiocytosis. Blood 2020; 136 (Supplement 1): 20
• Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, Degar B, Garrington TP, Sevilla J, Putti MC, Fagioli F, Ahlmann M, Dapena Diaz JL, Henry M, De Benedetti F, Grom A, Lapeyre G, Jacqmin P, Ballabio M, de Min C. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med. 2020 May 7;382(19):1811-1822. doi: 10.1056/NEJMoa1911326.

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2014
• Primary Completion (Actual): May 18, 2021
• Study Completion (Actual): May 18, 2021

Study Registration Dates

• First Submitted: December 23, 2013
• First Submitted That Met QC Criteria: February 20, 2014
• First Posted (Estimate): February 24, 2014

Study Record Updates

• Last Update Posted (Actual): June 28, 2022
• Last Update Submitted That Met QC Criteria: June 1, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Emapalumab; Hemophagocytic lymphohistiocytosis (HLH) previously treated with NI-0501
• Additional Relevant MeSH Terms: Lymphatic Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: NI-0501-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes