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)

• 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: Swedish Orphan Biovitrum
• Information provided by (Responsible Party): Swedish Orphan Biovitrum

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.

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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).

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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

More Information

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

• 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:

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