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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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ClinicalTrials.gov Identifier: NCT03311854
Recruitment Status : Completed
First Posted : October 17, 2017
Results First Posted : January 26, 2022
Last Update Posted : May 17, 2022
Sponsor:
Information provided by (Responsible Party):
Swedish Orphan Biovitrum

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.

Condition or disease Intervention/treatment Phase
Macrophage Activation Syndrome Lymphohistiocytosis, Hemophagocytic Arthritis, Juvenile Adult Onset Still Disease Drug: Emapalumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 20, 2018
Actual Primary Completion Date : May 19, 2020
Actual Study Completion Date : May 19, 2020


Arm Intervention/treatment
Experimental: Emapalumab Drug: Emapalumab
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).
Other Name: Gamifant




Primary Outcome Measures :
  1. Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) [ Time Frame: Up to Week 8 ]
  2. Evolution of Laboratory Parameters [ Time Frame: Up to Week 8 ]

    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

  3. Number of Participants Withdrawn Due to Safety Reasons [ Time Frame: Up to Week 8 ]
  4. Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment [ Time Frame: Week 8 ]

    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.

  5. Time to First MAS Remission [ Time Frame: Up to Week 8 ]
  6. Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study [ Time Frame: Up to Week 8 ]
    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).

  7. Time to Achievement of Permanent Glucocorticoids Tapering [ Time Frame: Up to Week 8 ]
    Time to achievement of permanent glucocorticoid tapering by at least 50% of the equivalent dose of prednisone administered at emapalumab treatment start.

  8. Survival Time [ Time Frame: Up to Week 8 ]
    Number of participants alive at the end of the study

  9. Number of Participants Withdrawn From the Study Due to Lack of Efficacy [ Time Frame: Up to Week 8 ]
    Number of participants withdrawn from the study due to lack of efficacy

  10. Levels of Emapalumab Concentration [ 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. ]
    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.

  11. Pharmacodynamic Parameters [ Time Frame: Up to Week 8 ]
    Levels of total INF-gamma, CXCL9 and CXCL10

  12. Number of Participants Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity [ Time Frame: Up to Week 8 ]
    The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   0 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03311854


Locations
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United States, Ohio
Cincinnati Children'S Hospital
Cincinnati, Ohio, United States, 45229
France
Hôpital Necker-Enfants Malades, Unité d'Immunologie-hématologie et Rhumatologie pédiatriques
Paris, France, 75743
Italy
IRCCS Ospedale Pediatrico, Bambino Gesù
Rome, Italy, 00165
Spain
Hospital Sant Joan de Deu
Barcelona, Spain, 08950
United Kingdom
Great Ormond Street Hospital for Children
London, United Kingdom, WC1N 3JH
Sponsors and Collaborators
Swedish Orphan Biovitrum
  Study Documents (Full-Text)

Documents provided by Swedish Orphan Biovitrum:
Study Protocol  [PDF] January 7, 2020
Statistical Analysis Plan  [PDF] April 22, 2021

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Responsible Party: Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier: NCT03311854    
Other Study ID Numbers: NI-0501-06
First Posted: October 17, 2017    Key Record Dates
Results First Posted: January 26, 2022
Last Update Posted: May 17, 2022
Last Verified: May 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Swedish Orphan Biovitrum:
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
Additional relevant MeSH terms:
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Arthritis
Arthritis, Juvenile
Still's Disease, Adult-Onset
Lymphohistiocytosis, Hemophagocytic
Macrophage Activation Syndrome
Syndrome
Disease
Pathologic Processes
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Arthritis, Rheumatoid
Lymphoproliferative Disorders
Immunoproliferative Disorders
Histiocytosis, Non-Langerhans-Cell
Histiocytosis
Lymphatic Diseases