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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

Primary Purpose

Hemophagocytic Lymphohistiocytosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Emapalumab
Sponsored by
Swedish Orphan Biovitrum
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Hemophagocytic Lymphohistiocytosis focused on measuring Hemophagocytic lymphohistiocytosis (HLH) previously treated with NI-0501, Emapalumab

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Spectrum Health Helen Devos Children's Hospital
  • University of North Carolina at Chapel Hill
  • Cincinnati Children's Hospital - Division of Immunobiology
  • Cincinnati Children's Hospital
  • Texas Children's Cancer Center
  • Hôpital Necker-Enfants Malades
  • Fondazione MBBM c/o Ospedale San Gerardo Clinica Pediatrica
  • Azienda Ospedaliera Padova
  • Ospedale Pediatrico Bambino Gesu - UO Reumatologia
  • Ospedale Pediatrico Bambino Gesu
  • Ospedale della Donna e del Bambino - U.O.C. Oncoematologia Pediatrica
  • Hospital Universitario Vall d'Hebron Servei de Hematologia i Oncologia
  • Sant Joan de Déu Hospital - Pediatric Rheumatology Department
  • Hospital Universitario Niño Jesús Servicio de Hemato-Oncología Pediátrica
  • UCL Institute of Child Health Great Ormond Street Hospital
  • Great Ormond Street Hospital - Department of Haematology

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

No Intervention

Other

Arm Label

Enrolled-04 Cohort

Enrolled-06 Cohort

Enrolled-CU Cohort

Arm Description

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.

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).

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
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.
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.
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.
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.
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%.
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.
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.
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).
Circulating Emapalumab Level (Enrolled-06 Cohort)
Total Human Interferon Gamma Levels (Enrolled-04 Cohort)
Total Human Interferon Gamma Levels (Enrolled-06 Cohort)
Number of Participants With Anti-drug Antibody

Full Information

First Posted
December 23, 2013
Last Updated
June 1, 2022
Sponsor
Swedish Orphan Biovitrum
Collaborators
Seventh Framework Programme
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1. Study Identification

Unique Protocol Identification Number
NCT02069899
Brief Title
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
Official Title
A Multicenter Study for the Long-term Follow-up of HLH Patients Who Received Treatment With NI-0501, an Anti-interferon Gamma Monoclonal Antibody
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
August 4, 2014 (Actual)
Primary Completion Date
May 18, 2021 (Actual)
Study Completion Date
May 18, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Swedish Orphan Biovitrum
Collaborators
Seventh Framework Programme

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophagocytic Lymphohistiocytosis
Keywords
Hemophagocytic lymphohistiocytosis (HLH) previously treated with NI-0501, Emapalumab

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Enrolled-04 Cohort
Arm Type
Other
Arm Description
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.
Arm Title
Enrolled-06 Cohort
Arm Type
No Intervention
Arm Description
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).
Arm Title
Enrolled-CU Cohort
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Emapalumab
Other Intervention Name(s)
NI-0501
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Event (AE)
Description
Adverse events were defined as any undesirable experience occurring in a participant during the study, whether or not considered related to emapalumab.
Time Frame
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 Measure Information:
Title
Cumulative Duration of Response (Enrolled-04 Cohort)
Description
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).
Time Frame
From 1st achievement of overall response until HSCT or last treatment date if participant did not undergo HSCT (maximum 250 days)
Title
Duration of First Response (Enrolled-06 Cohort)
Description
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.
Time Frame
From first date of response and first date of loss of response or death (maximum 416 days)
Title
Overall Survival (Enrolled-04 Cohort)
Description
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.
Time Frame
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)
Title
Overall Survival (Enrolled-06 Cohort)
Description
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.
Time Frame
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)
Title
Percentage of Participants Who Achieved Engraftment (Enrolled-04 Cohort)
Description
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.
Time Frame
From HSCT up to 12 months
Title
Percentage of Participants Who Achieved Donor Chimerism (Enrolled-04 Cohort)
Description
For participants who underwent HSCT, achievement of donor chimerism was considered based on donor chimerism in peripheral blood completed, that is, donor cells >95%.
Time Frame
From HSCT to 12 months
Title
Percentage of Participants With Graft-versus-host-disease (Enrolled-04 Cohort)
Description
Occurrence of graft-versus-host-disease, reported in Study NI-0501-05 as an AE.
Time Frame
From HSCT to 12 months
Title
MAS Activity Level as Assessed by Visual Analogue Scale (Enrolled-06 Cohort)
Description
MAS activity was monitored using a visual analogue scale ranging from 0 to 10 with a higher score indicted higher disease activity.
Time Frame
Baseline (first NI-0501-05 visit), Day 100, Month 12/End of Study
Title
Circulating Emapalumab Level (Enrolled-04 Cohort)
Description
Circulating Emapalumab level in Enrolled-04 Cohort who continued to receive treatment with emapalumab in the current study (NI-0501-05).
Time Frame
First infusion day (infusion duration: 1-2 hours) in Study NI-0501-05, last infusion day (infusion Day 188), 12 months post-transplant
Title
Circulating Emapalumab Level (Enrolled-06 Cohort)
Time Frame
Baseline (first NI-0501-05 visit), Day 100, Month 6
Title
Total Human Interferon Gamma Levels (Enrolled-04 Cohort)
Time Frame
First infusion day (infusion duration: 1-2 hours) in Study NI-0501-05, Day 100 post-transplant, 12 months post-transplant
Title
Total Human Interferon Gamma Levels (Enrolled-06 Cohort)
Time Frame
Baseline (first NI-0501-05 visit), Day 100, Month 12/End of Study
Title
Number of Participants With Anti-drug Antibody
Time Frame
From enrolment up to 12 months post-transplant or last emapalumab infusion (maximum 639 days)

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Spectrum Health Helen Devos Children's Hospital
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49503
Country
United States
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Cincinnati Children's Hospital - Division of Immunobiology
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
Cincinnati Children's Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Texas Children's Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Hôpital Necker-Enfants Malades
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
Fondazione MBBM c/o Ospedale San Gerardo Clinica Pediatrica
City
Monza
ZIP/Postal Code
20900
Country
Italy
Facility Name
Azienda Ospedaliera Padova
City
Padova
ZIP/Postal Code
35128
Country
Italy
Facility Name
Ospedale Pediatrico Bambino Gesu - UO Reumatologia
City
Rome
ZIP/Postal Code
00165
Country
Italy
Facility Name
Ospedale Pediatrico Bambino Gesu
City
Rome
ZIP/Postal Code
00165
Country
Italy
Facility Name
Ospedale della Donna e del Bambino - U.O.C. Oncoematologia Pediatrica
City
Verona
ZIP/Postal Code
37126
Country
Italy
Facility Name
Hospital Universitario Vall d'Hebron Servei de Hematologia i Oncologia
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Sant Joan de Déu Hospital - Pediatric Rheumatology Department
City
Barcelona
ZIP/Postal Code
08950
Country
Spain
Facility Name
Hospital Universitario Niño Jesús Servicio de Hemato-Oncología Pediátrica
City
Madrid
ZIP/Postal Code
28009
Country
Spain
Facility Name
UCL Institute of Child Health Great Ormond Street Hospital
City
London
ZIP/Postal Code
WC1N1EH
Country
United Kingdom
Facility Name
Great Ormond Street Hospital - Department of Haematology
City
London
ZIP/Postal Code
WC1N3JH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
Citation
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.
Results Reference
result
Citation
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
Results Reference
result
PubMed Identifier
32374962
Citation
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.
Results Reference
result

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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

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