Back to resultsA Study to Investigate the Safety and Efficacy of Emapalumab, an Anti-IFN-gamma mAb in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
Primary Purpose
Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Emapalumab
Sponsored by
About this trial
This is an interventional treatment trial for Macrophage Activation Syndrome focused on measuring Emapalumab, Gamifant, Macrophage activation syndrome, Secondary hemophagocytic lymphohistiocytosis, Interferon-gamma, Systemic juvenile idiopathic arthritis, Adult-onset Still's disease, MAS, HLH, sHLH, IFN-gamma, IFNγ, sJIA, AOSD, NI-0501-06, NI-0501
Eligibility Criteria
Inclusion Criteria:
- Patients of both genders
- For sJIA patients: Confirmed sJIA diagnosis. For patients presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility. For AOSD patients: confirmed AOSD diagnosis as per Yamaguchi criteria.
- Diagnosis of active MAS.
- An inadequate response to high dose i.v. glucocorticoid treatment administered for at least 3 days as per local standard of care (including but not limited to pulses of 30 mg/kg PDN on 3 consecutive days). High dose i.v. glucocorticoid should not be lower than 2 mg/kg/day of PDN equivalent in 2 divided doses (or at least 60 mg/day in patients of 30 kg or more). In case of rapid worsening of the patient's condition and/or lab parameters, inclusion may occur within less than 3 days from starting high dose i.v. glucocorticoids.
- Tocilizumab, TNF inhibitors and canakinumab, if administered, have to be discontinued before emapalumab initiation.
- 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. Males with partners(s) of child-bearing potential must agree to take appropriate precautions.
- Informed consent provided 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.
Exclusion Criteria:
- Diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease.
- Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections.
- Clinical suspicion of latent tuberculosis.
- Positive serology for HIV antibodies.
- Presence of malignancy.
- Patients who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, CNS, liver or renal function that in the opinion of the Investigator may significantly affect likelihood to respond to treatment and/or assessment of emapalumab safety.
- History of hypersensitivity or allergy to any component of the study drug
- Receipt of a BCG vaccine within 12 weeks prior to screening.
- Receipt of live or attenuated live vaccines (other than BCG) within 6 weeks prior to screening.
- Pregnant or lactating female patients.
Sites / Locations
- Cincinnati Children'S Hospital
- Hôpital Necker-Enfants Malades, Unité d'Immunologie-hématologie et Rhumatologie pédiatriques
- IRCCS Ospedale Pediatrico, Bambino Gesù
- Hospital Sant Joan de Deu
- Great Ormond Street Hospital for Children
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Emapalumab
Arm Description
Outcomes
Primary Outcome Measures
Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious)
Evolution of Laboratory Parameters
Shifts from baseline in the following MAS-relevant laboratory parameters are reported:
Leukocytes
Platelets
Lactate dehydrogenase (LDH)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Ferritin
C-reactive protein
Activated partial thromboplastin time (aPTT)
Prothrombin time
D-dimer
Fibrinogen
Number of Participants Withdrawn Due to Safety Reasons
Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment
Remission from MAS was evaluated according to the following criteria:
Resolution of clinical signs and symptoms according to the investigator (MAS clinical signs and symptoms activity score ≤ 1)
and
Normalization of laboratory parameters relevant to MAS, as follows:
WBC count and platelet count above the LLN.
LDH below 1.5 × the ULN.
ALT and AST both below 1.5 × the ULN.
Fibrinogen higher than 100 mg/dL.
Ferritin levels decreased by at least 80 % from values at screening or baseline (whichever was higher) or below 2000 ng/mL, whichever was lower.
Time to First MAS Remission
Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study
Permanently tapering by at least 50% of the equivalent dose of prednisone. This was defined as achieving reduction of 50% of the baseline dose [SD0] and maintaining the reduction until the end of study).
Time to Achievement of Permanent Glucocorticoids Tapering
Time to achievement of permanent glucocorticoid tapering by at least 50% of the equivalent dose of prednisone administered at emapalumab treatment start.
Survival Time
Number of participants alive at the end of the study
Number of Participants Withdrawn From the Study Due to Lack of Efficacy
Number of participants withdrawn from the study due to lack of efficacy
Levels of Emapalumab Concentration
On all infusion days, PK samples were collected before the infusion start and between 15 and 30 minutes after infusion completion. In addition, following the first emapalumab infusion, PK samples were collected approximately 24 and 48 hours post-infusion, and following the second emapalumab infusion, PK samples were collected approximately 48 hours post-infusion. Upon treatment completion, PK samples were collected on all non-infusion visits until the 4-week follow-up visit/EOS.
Pharmacodynamic Parameters
Levels of total INF-gamma, CXCL9 and CXCL10
Number of Participants Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity
The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03311854
Brief Title
A Study to Investigate the Safety and Efficacy of Emapalumab, an Anti-IFN-gamma mAb in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
Official Title
A Pilot, Open-label, Single Arm, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Administrations of Emapalumab, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
February 20, 2018 (Actual)
Primary Completion Date
May 19, 2020 (Actual)
Study Completion Date
May 19, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Swedish Orphan Biovitrum
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Macrophage Activation Syndrome (MAS) is a rare, life-threatening condition characterized by uncontrolled hyperinflammation which may develop on the background of systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD). Emapalumab is a monoclonal antibody neutralizing interferon-gamma (IFN-gamma), a key cytokine which contributes to the inflammation and tissue damage seen in MAS. The purpose of this study is to assess the safety, tolerability and efficacy of emapalumab in sJIA or AOSD participants developing MAS, presenting an inadequate response to high dose glucocorticoid treatment.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile, Adult Onset Still Disease
Keywords
Emapalumab, Gamifant, Macrophage activation syndrome, Secondary hemophagocytic lymphohistiocytosis, Interferon-gamma, Systemic juvenile idiopathic arthritis, Adult-onset Still's disease, MAS, HLH, sHLH, IFN-gamma, IFNγ, sJIA, AOSD, NI-0501-06, NI-0501
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Emapalumab
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Emapalumab
Other Intervention Name(s)
Gamifant
Intervention Description
Emapalumab was administered at an initial dose of 6 mg/kg by intravenous infusion. Emapalumab treatment continued at a dose of 3 mg/kg, every 3 days until study day 15, and then twice-a-week for an additional 2 weeks, i.e., until study day 28. The emapalumab regimen could be adapted (the frequency between infusions shortened, the dose increased, or the treatment prolonged beyond 4 weeks) upon assessment of a favourable benefit-risk profile. There was a 4-week off-drug follow-up period (up to Week 8).
Primary Outcome Measure Information:
Title
Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious)
Time Frame
Up to Week 8
Title
Evolution of Laboratory Parameters
Description
Shifts from baseline in the following MAS-relevant laboratory parameters are reported:
Leukocytes
Platelets
Lactate dehydrogenase (LDH)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Ferritin
C-reactive protein
Activated partial thromboplastin time (aPTT)
Prothrombin time
D-dimer
Fibrinogen
Time Frame
Up to Week 8
Title
Number of Participants Withdrawn Due to Safety Reasons
Time Frame
Up to Week 8
Title
Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment
Description
Remission from MAS was evaluated according to the following criteria:
Resolution of clinical signs and symptoms according to the investigator (MAS clinical signs and symptoms activity score ≤ 1)
and
Normalization of laboratory parameters relevant to MAS, as follows:
WBC count and platelet count above the LLN.
LDH below 1.5 × the ULN.
ALT and AST both below 1.5 × the ULN.
Fibrinogen higher than 100 mg/dL.
Ferritin levels decreased by at least 80 % from values at screening or baseline (whichever was higher) or below 2000 ng/mL, whichever was lower.
Time Frame
Week 8
Title
Time to First MAS Remission
Time Frame
Up to Week 8
Title
Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study
Description
Permanently tapering by at least 50% of the equivalent dose of prednisone. This was defined as achieving reduction of 50% of the baseline dose [SD0] and maintaining the reduction until the end of study).
Time Frame
Up to Week 8
Title
Time to Achievement of Permanent Glucocorticoids Tapering
Description
Time to achievement of permanent glucocorticoid tapering by at least 50% of the equivalent dose of prednisone administered at emapalumab treatment start.
Time Frame
Up to Week 8
Title
Survival Time
Description
Number of participants alive at the end of the study
Time Frame
Up to Week 8
Title
Number of Participants Withdrawn From the Study Due to Lack of Efficacy
Description
Number of participants withdrawn from the study due to lack of efficacy
Time Frame
Up to Week 8
Title
Levels of Emapalumab Concentration
Description
On all infusion days, PK samples were collected before the infusion start and between 15 and 30 minutes after infusion completion. In addition, following the first emapalumab infusion, PK samples were collected approximately 24 and 48 hours post-infusion, and following the second emapalumab infusion, PK samples were collected approximately 48 hours post-infusion. Upon treatment completion, PK samples were collected on all non-infusion visits until the 4-week follow-up visit/EOS.
Time Frame
Data from the following time points are presented: SD0 (pre- and post-dose), Week 4 Visit 2 (pre- and post-dose), and 4-week follow-up visit/EoS.
Title
Pharmacodynamic Parameters
Description
Levels of total INF-gamma, CXCL9 and CXCL10
Time Frame
Up to Week 8
Title
Number of Participants Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity
Description
The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).
Time Frame
Up to Week 8
10. Eligibility
Sex
All
Minimum Age & Unit of Time
0 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients of both genders
For sJIA patients: Confirmed sJIA diagnosis. For patients presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility. For AOSD patients: confirmed AOSD diagnosis as per Yamaguchi criteria.
Diagnosis of active MAS.
An inadequate response to high dose i.v. glucocorticoid treatment administered for at least 3 days as per local standard of care (including but not limited to pulses of 30 mg/kg PDN on 3 consecutive days). High dose i.v. glucocorticoid should not be lower than 2 mg/kg/day of PDN equivalent in 2 divided doses (or at least 60 mg/day in patients of 30 kg or more). In case of rapid worsening of the patient's condition and/or lab parameters, inclusion may occur within less than 3 days from starting high dose i.v. glucocorticoids.
Tocilizumab, TNF inhibitors and canakinumab, if administered, have to be discontinued before emapalumab initiation.
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. Males with partners(s) of child-bearing potential must agree to take appropriate precautions.
Informed consent provided 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.
Exclusion Criteria:
Diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease.
Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections.
Clinical suspicion of latent tuberculosis.
Positive serology for HIV antibodies.
Presence of malignancy.
Patients who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, CNS, liver or renal function that in the opinion of the Investigator may significantly affect likelihood to respond to treatment and/or assessment of emapalumab safety.
History of hypersensitivity or allergy to any component of the study drug
Receipt of a BCG vaccine within 12 weeks prior to screening.
Receipt of live or attenuated live vaccines (other than BCG) within 6 weeks prior to screening.
Pregnant or lactating female patients.
Facility Information:
Facility Name
Cincinnati Children'S Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Hôpital Necker-Enfants Malades, Unité d'Immunologie-hématologie et Rhumatologie pédiatriques
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
IRCCS Ospedale Pediatrico, Bambino Gesù
City
Rome
ZIP/Postal Code
00165
Country
Italy
Facility Name
Hospital Sant Joan de Deu
City
Barcelona
ZIP/Postal Code
08950
Country
Spain
Facility Name
Great Ormond Street Hospital for Children
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
A Study to Investigate the Safety and Efficacy of Emapalumab, an Anti-IFN-gamma mAb in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
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