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)

NCT03311854 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: NI-0501-06
• Study Type: interventional
• Target: 14
• Locations: 5 countries
• Sites: 5

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.

Conditions

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

Outcome Measures

Primary Outcomes (12)

• Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious)

  Up to Week 8

• 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

  Up to Week 8

• Number of Participants Withdrawn Due to Safety Reasons

  Up to Week 8

• 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.

  Week 8

• Time to First MAS Remission

  Up to Week 8

• 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).

  Up to Week 8

• 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.

  Up to Week 8

• Survival Time

  Number of participants alive at the end of the study

  Up to Week 8

• Number of Participants Withdrawn From the Study Due to Lack of Efficacy

  Number of participants withdrawn from the study due to lack of efficacy

  Up to Week 8

• 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.

  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.

• Pharmacodynamic Parameters

  Levels of total INF-gamma, CXCL9 and CXCL10

  Up to Week 8

• 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).

  Up to Week 8

Study Arms (1)

Emapalumab

EXPERIMENTAL

Drug: Emapalumab

Interventions

Emapalumab DRUG

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).

Also known as: Gamifant

Emapalumab

Eligibility Criteria

• Age: 0 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Swedish Orphan Biovitrum: lead

Study Sites (5)

Cincinnati Children'S Hospital

Cincinnati, Ohio, 45229, United States

Location

Hôpital Necker-Enfants Malades, Unité d'Immunologie-hématologie et Rhumatologie pédiatriques

Paris, 75743, France

Location

IRCCS Ospedale Pediatrico, Bambino Gesù

Rome, 00165, Italy

Location

Hospital Sant Joan de Deu

Barcelona, 08950, Spain

Location

Great Ormond Street Hospital for Children

London, WC1N 3JH, United Kingdom

Location

Related Publications (2)

• Brossard P, Laveille C. Population Pharmacokinetics of the Anti-Interferon-Gamma Monoclonal Antibody Emapalumab: An Updated Analysis. Rheumatol Ther. 2024 Jun;11(3):869-880. doi: 10.1007/s40744-024-00669-y. Epub 2024 Apr 25.

  PMID: 38662147 DERIVED

• De Benedetti F, Grom AA, Brogan PA, Bracaglia C, Pardeo M, Marucci G, Eleftheriou D, Papadopoulou C, Schulert GS, Quartier P, Anton J, Laveille C, Frederiksen R, Asnaghi V, Ballabio M, Jacqmin P, de Min C. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis. 2023 Jun;82(6):857-865. doi: 10.1136/ard-2022-223739. Epub 2023 Mar 31.

  PMID: 37001971 DERIVED

MeSH Terms

Conditions

Macrophage Activation Syndrome; Lymphohistiocytosis, Hemophagocytic; Arthritis, Juvenile; Still's Disease, Adult-Onset

Interventions

Emapalumab

Condition Hierarchy (Ancestors)

Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Arthritis, Rheumatoid

Results Point of Contact

• Title: Veronica Asnaghi, MD
• Organization: Sobi AG

veronica.asnaghi@sobi.com

+41 61 201 13 20

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2017
• First Posted: October 17, 2017
• Study Start: February 20, 2018
• Primary Completion: May 19, 2020
• Study Completion: May 19, 2020
• Last Updated: May 17, 2022
• Results First Posted: January 26, 2022

Record last verified: 2022-05

Locations

US (1); GB (1); ES (1); IT (1); FR (1)