Evaluate Efficacy, Safety and Tolerability, PK and PD of Emapalumab in Children and Adults With MAS in Still's or SLE (EMERALD)

A Two-cohort, Open-label, Single Arm, Multicenter Study to Evaluate Efficacy, Safety and Tolerability, PK and PD, of Emapalumab in Children and Adults With MAS in Still's Disease or With MAS in Systemic Lupus Erythematous

The purpose of this study is to assess the safety, tolerability and efficacy of emapalumab in children and adults with macrophage activation syndrome (sHLH/MAS) in Still's disease (including systemic juvenile idiopathic arthritis and adult onset Still's disease) or with sHLH/MAS in systemic lupus erythematous, resenting an inadequate response to high dose glucocorticoid treatment.

Study Overview

• Status: Recruiting
• Conditions: Systemic Lupus Erythematosus; Macrophage Activation Syndrome; Still Disease; Secondary Hemophagocytic Lymphohistiocytosis; SJIA; AOSD; MAS
• Intervention / Treatment: Drug: Emapalumab

Detailed Description

Study NI-0501-14 is a two-cohort trial that enrolls subjects who are diagnosed with sHLH/MAS (MAS being a form of secondary HLH) and who are presenting an inadequate response to high doses of GCs. These subjects will be enrolled in 2 cohorts as per their background disease. The cohorts are defined as follows:

• Cohort 1: MAS in the context of sJIA and AOSD.
• Cohort 2: MAS in the context of pediatric and adult SLE.

The study has the objectives to investigate the efficacy, safety and tolerability, for 8 weeks, and PK and PD, QoL and immunogenicity in these 2 cohorts for up to 1 year after last dose of of emapalumab.

Macrophage Activation Syndrome (MAS) Secondary Hemophagocytic Lymphohistiocytosis (sHLH) systemic Juvenile Idiopathic Arthritis (sJIA) Adult-onset Still's Disease (AOSD) Systemic Lupus Erythematosus (SLE)

• Study Type: Interventional
• Enrollment (Estimated): 41
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anna Westerdahl; Email: Anna.Westerdahl@sobi.com
• Study Contact Backup: Name: Adnan Mahmood, MD; Phone Number: +46(0)8 697 20 00; Email: Adnan.Mahmood@sobi.com

Study Locations

• Belgium
  • Leuven, Belgium
    • Recruiting
    • Universitair Ziekenhuis Leuven
    • Contact: Dr. De Somer, MD
• Canada
  • Calgary, Canada
    • Recruiting
    • Alberta Children's Hospital
    • Contact: Dr. Benseler, MD
  • Calgary, Canada
    • Recruiting
    • University of Calgary
    • Contact: Dr. MacMullan, MD
  • Montréal, Canada
    • Recruiting
    • Centre Hospitalier de l'Université de Montréal
    • Contact: Dr. Chapdelaine, MD
  • Montréal, Canada
    • Recruiting
    • Centre Hospitalier Universitaire Sainte-Justine
    • Contact: Dr. Decaluwe, MD
  • Toronto, Canada
    • Recruiting
    • Hospital For Sick Children
    • Contact: Dr. Levy, MD
• China
  • Beijing, China
    • Recruiting
    • Beijing Friendship Hospital
    • Contact: Dr. Wang, MD
  • Beijing, China
    • Recruiting
    • Beijing Children's Hospital
    • Contact: Dr. Li, MD
  • Shanghai, China
    • Recruiting
    • Children's Hospital of Fudan University
    • Contact: Dr. Sun, MD
• Czechia
  • Olomouc, Czechia
    • Recruiting
    • Fakultní nemocnice Olomouc
    • Contact: Dr. Bouchalova, MD
  • Praha, Czechia
    • Recruiting
    • Vseobecna fakultni nemocnice v Praze
    • Contact: Dr. Dolezalova, MD
• France
  • Lille, France
    • Recruiting
    • Hopital Claude Huriez
    • Contact: Dr. Hachulla, MD
    • Contact: Dr. Terriou, MD
  • Marseille, France
    • Recruiting
    • Hôpital de la Conception
    • Contact: Dr. Kaplanski, MD
  • Paris, France
    • Recruiting
    • Hopital Universitaire Pitie Salpetriere
    • Contact: Dr. Fautrel, MD
  • Paris, France
    • Recruiting
    • Hôpital Necker-Enfants Malades
    • Contact: Dr. Quartier, MD
• Germany
  • Berlin, Germany
    • Recruiting
    • Charité Universitätsmedizin
    • Contact: Dr. Biesen, MD
  • Heidelberg, Germany
    • Recruiting
    • Universitätsklinikum Heidelberg
    • Contact: Dr. Blank, MD
• Italy
  • Genova, Italy
    • Recruiting
    • IRCCS G. Gaslini
    • Contact: Dr. Gattorno, MD
  • Milano, Italy
    • Recruiting
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
    • Contact: Dr. Filocamo, MD
  • Roma, Italy
    • Recruiting
    • Ospedale Pediatrico Bambino Gesu
    • Contact: Dr. De Benedetti, MD
  • Trieste, Italy
    • Recruiting
    • IRCCS - Materno-Infantile Burlo Garofolo
    • Contact: Dr. Tommasini, MD
• Japan
  • Kawasaki, Japan
    • Recruiting
    • St. Marianna University School of Medicine Hospital
    • Contact: Dr. Mori, MD
  • Takatsuki, Japan
    • Recruiting
    • Osaka Medical and Pharmaceutical University Hospital
    • Contact: Dr. Ozeki, MD
  • Tokyo, Japan
    • Recruiting
    • Tokyo Medical and Dental University Hospital
    • Contact: Dr. Shimizu, MD
  • Yokohama, Japan
    • Recruiting
    • Yokohama City University Hospital
    • Contact: Dr. Ito, MD
• Netherlands
  • Utrecht, Netherlands
    • Recruiting
    • UMC Utrecht
    • Contact: Dr. Vastert, MD
• Poland
  • Kraków, Poland
    • Recruiting
    • Szpital Specjalistyczny im. J. Dietla w Krakowie
    • Contact: Pr. Dr. Batko, MD
  • Kraków, Poland
    • Recruiting
    • Wojewódzki Specjalistyczny Szpital Dzieciecy im. Sw. Ludwika w Krakowie
    • Contact: Dr Zuber, MD
  • Poznań, Poland
    • Recruiting
    • Ortopedyczno - Rehabilitacyjny Szpital Kliniczny im. Wiktora Degi Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
    • Contact: Dr. Samborski, MD
• Spain
  • Barcelona, Spain
    • Recruiting
    • Hospital Sant Joan de Déu
    • Contact: Dr. Antón López, MD
  • La Paz, Spain
    • Recruiting
    • Hospital Universitario
    • Contact: Dr. Robles-Marhuenda, MD
  • La Paz, Spain
    • Terminated
    • Hospital Universitario La Paz
  • Valencia, Spain
    • Recruiting
    • Hospital Universitari i Politecnic La Fe
    • Contact: Dr. Calvo Penade, MD
• Sweden
  • Stockholm, Sweden
    • Recruiting
    • Karolinska Universitetssjukhuset Solna
    • Contact: Dr. Faustini, MD
  • Stockholm, Sweden
    • Recruiting
    • Karolinska Universitetssjukhuset Solna (Ped. Rheum.)
    • Contact: Dr. Horne, MD
• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Great Ormond Street Hospital
    • Contact: Dr. Brogan, MD
  • London, United Kingdom
    • Recruiting
    • Imperial College Healthcare NHS Trust
    • Contact: Dr. Youngstein, MD
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • UAB Hospital
      • Contact: Dr. Rubio, MD
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • UCLA Health
      • Contact: Dr. McCurdy, MD
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida
      • Contact: Dr. Elder, MD
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Recruiting
      • Children's Healthcare of Atlanta
      • Contact: Dr. Chandrakasan, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Withdrawn
      • Boston Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota Masonic Children's Hospital
      • Contact: Dr. Binstadt, MD
  • Ohio
    • Akron, Ohio, United States, 44308
      • Recruiting
      • Akron Children's Hospital
      • Contact: Dr. Cook, MD
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Dr. Grom, MD
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital, Abigail Wexner Research Institute
      • Contact: Dr. Akoghlanian, MD
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC Children's Hospital of Pittsburgh
      • Contact: Dr. Rosenkranz, MD
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Recruiting
      • Primary Children's Hospital
      • Contact: Dr. Hersh, MD
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • Rheumatology Clinic at University of Washington Medical Center - Roosevelt
      • Contact: Dr Singh, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria Run-in phase in all cohorts

1. Informed consent provided by the subject or by the subject s' legally authorized representative(s) with the assent of subjects who are legally capable of providing it, as required by local law.
2. Male and female subjects aged between 6 months and 80 years of age at the time of diagnosis of MAS.
3. MAS defined as per the criteria defined below for each cohort and requiring treatment with GCs.

Interventional phase in all cohorts

1. Informed consent provided by the subject or by the subject's legally authorized representative(s) with the assent of subjects who are legally capable of providing it, as as required by local law.
2. Male and female subjects aged between 6 months and 80 years of age at the time of diagnosis of active MAS.
3. Subjects who have shown an inadequate response to high dose intravenous (i.v.) GCs administered for at least 3 days according to local standard clinical practice, including but not limited to pulses of 30 mg/kg PDN on 3 consecutive days. High i.v. GCs dose is recommended not to be lower than 2 mg/kg/ day PDN equivalent (or at least 60 mg/day in pediatric subjects of 30 kg or more, and at least 1g/day in adult MAS subjects). In case of rapid worsening of the subject's condition and/or laboratory parameters, as per Investigator judgment, inclusion may occur within less than 3 days from starting high dose GCs.

4. Diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the followings:

   a. Febrile subjects presenting with ferritin > 684 ng/mL. b. and any 2 of: i. Platelet count ≤ 181 x109/L ii. AST-level > 48 U/L iii. Triglycerides > 156 mg/dL iv. Fibrinogen level ≤ 360 mg/dL

5. Female subjects of child-bearing potential willing to use highly effective methods of contraception from study drug initiation to 6 months after the last dose of study drug.

   Specific inclusion criteria to Cohort 1 and Cohort 2

6. Cohort 1:

   1. Confirmed sJIA diagnosis. For subjects presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility.
   2. Confirmed diagnosis of AOSD as per Yamaguchi criteria.

7. Cohort 2:

   1. Confirmed diagnosis of SLE as per SLICC'12 criteria.

Exclusion criteria

1. Primary HLH documented by either the presence of a known causative genetic mutation or abnormal perforin expression and CD107a degranulation assay as described with primary hemophagocytic lymphohistiocytosis or by the presence of family history.
2. Confirmed malignancy. Note: subjects with a suspected malignancy should have mononuclear cells typed by flow cytometry and/or tissue biopsy, as applicable, to rule out malignancy.
3. Treatment with canakinumab, JAK inhibitors, TNF inhibitors and tocilizumab at the time of emapalumab initiation.
4. Ongoing treatment with anakinra at a dose above 4 mg/kg at time of emapalumab initiation.
5. Subjects treated with etoposide for MAS in the last 1 month.
6. Clinically active mycobacteria (typical and atypical), Histoplasma Capsulatum, or Salmonella infections.
7. Evidence of leishmania infections.
8. Evidence of latent tuberculosis.
9. History of hypersensitivity or allergy to any component of the study drug.
10. Receipt of a Bacillus Calmette-Guerin (BCG) vaccine within 12 weeks prior to screening.
11. Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to screening.
12. Pregnancy or lactating female subjects.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (sJIA and AOSD) and Cohort 2 (SLE); MAS in the context of systemic juvenile idiopathic arthritis and adult onset Still's disease (sJIA and AOSD) or SLE	Drug: Emapalumab; Emapalumab iv infusion; Other Names: NI-0501; emapalumab-lzsg; ATC code: L04AA39 (WHO)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with complete response (CR) at Week 8 after first administration of emapalumab	Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm. Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm. Clinical signs will be considered as resolved if VAS is below or equal to 1/10. And Normalization of laboratory parameters relevant to MAS, as follows: WBC above LLN platelet count above LLN LDH below 1.5 ULN ALT below 1.5 ULN AST below 1.5 ULN fibrinogen higher than 100 mg/dL ferritin levels decreased by at least 80 % from values at screening or baseline (whichever is higher) or below 2000 ng/ml, whichever is low	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GCs tapering to a dose below 50% of prednisolone (PDN) equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of MAS whichever occurs first	GC tapering as per investigator discretion	At any time in the study, up to 1 year
GCs tapering to ≤1mg/kg/day of PDN equivalent at any time during the study.	GC tapering as per investigator discretion	At any time in the study, up to 1 year
Time to achieve GCs tapering as defined above.	GC tapering as per investigator discretion	At any time in the study, up to 1 year
Time to first Complete Remission	Time to CR	At any time in the study, up to 1 year
Proportion of subjects with overall response as defined by CR or PR	Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm.	At any time in the study, up to 1 year
Time to first overall response as defined by CR or PR	CR defined as below: Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm.	At any time in the study, up to 1 year
MAS recurrence at anytime after achievement of CR	Time to MAS recurrence after CR	At any time after CR, up to 1 year
Withdrawal from the study due to lack of response as per Investigator decision	Time to withdrawal	At any time in the study, up to 1 year
Survival time	Time to Survival	At any time in the study, up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs) (serious and non-serious).	Incidence, severity, causality and outcomes of AEs	At any time in the study, up to 1 year
Study interruption due to safety reasons	Number of subjects withdrawn due to safety reasons	At any time in the study, up to 1 year
Laboratory parameters	Changes from baseline	At any time in the study, up to 1 year
Patient reported outcomes : PedsQL™;	Pediatric Quality of Life Inventory (PedsQL™; Generic Core Scales and Infant Scales, Acute versions)	Screening, Week 8, month 6 and 1 year
Patient reported outcomes: Patient/Parent Global Impression of Severity	Health-related quality of life: Global Assessment: Patient/Parent Global Impression of Severity	Screening, Week 8, month 6 and 1 year
Patient reported outcomes: Clinician Global Impression of Severity	Health-related quality of life: Global Assessment: Clinician Global Impression of Severity	Screening, Week 8, month 6 and 1 year
PK endpoints	Serum concentrations of emapalumab vs. time	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PK endpoints CEOI,	PK parameters by non-compartmental analysis: CEOI,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PK endpoints: λz,	PK parameters by non-compartmental analysis: λz,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PK endpoints: CL,	PK parameters by non-compartmental analysis: CL,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PK endpoints: Vss,	PK parameters by non-compartmental analysis: Vss,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PK endpoints: MRTlast and MRTinf	PK parameters by non-compartmental analysis: MRTlast and MRTinf, as applicable	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PD endpoints per cohort: free IFN-γ and total IFNγ	• Levels of circulating free IFN-γ at pre-dose, and total IFNγ (free IFN-γ+bound to emapalumab) after initiation of the study drug.	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PD endpoints per cohort: chemokines	Levels of the main IFN-γ-induced chemokines (CXCL9, CXCL10).	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
PD endpoints per cohort: sCD25)	Levels of MAS markers (sCD25).	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Immunogenicity endpoints	Occurrence of ADAs, Nab to emapalumab	Treatment visit 1, week 8, 6 months, 1 year

Collaborators and Investigators

• Sponsor: Swedish Orphan Biovitrum
• Investigators: Study Director: Brian Jamieson, MD, Swedish Orphan Biovitrum

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2021
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: June 16, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 12, 2021

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Autoimmune Diseases; Connective Tissue Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lupus Erythematosus, Systemic; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome
• Other Study ID Numbers: NI-0501-14; 2021-001577-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No