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

• ClinicalTrials.gov Identifier: NCT05001737
• Recruitment Status: Recruiting
• First Posted: August 12, 2021
• Last Update Posted: April 6, 2023
• Sponsor: Swedish Orphan Biovitrum
• Information provided by (Responsible Party): Swedish Orphan Biovitrum

Tracking Information

• First Submitted Date: June 16, 2021
• First Posted Date: August 12, 2021
• Last Update Posted Date: April 6, 2023
• Actual Study Start Date: December 15, 2021
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 3, 2021)

Proportion of subjects with complete response (CR) at Week 8 after first administration of emapalumab [ Time Frame: 8 weeks ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 3, 2021)

• 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 [ Time Frame: At any time in the study, up to 1 year ]
  GC tapering as per investigator discretion
• GCs tapering to ≤1mg/kg/day of PDN equivalent at any time during the study. [ Time Frame: At any time in the study, up to 1 year ]
  GC tapering as per investigator discretion
• Time to achieve GCs tapering as defined above. [ Time Frame: At any time in the study, up to 1 year ]
  GC tapering as per investigator discretion
• Time to first Complete Remission [ Time Frame: At any time in the study, up to 1 year ]
  Time to CR
• Proportion of subjects with overall response as defined by CR or PR [ Time Frame: At any time in the study, up to 1 year ]
  Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm.
• Time to first overall response as defined by CR or PR [ Time Frame: At any time in the study, up to 1 year ]
  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.
• MAS recurrence at anytime after achievement of CR [ Time Frame: At any time after CR, up to 1 year ]
  Time to MAS recurrence after CR
• Withdrawal from the study due to lack of response as per Investigator decision [ Time Frame: At any time in the study, up to 1 year ]
  Time to withdrawal
• Survival time [ Time Frame: At any time in the study, up to 1 year ]
  Time to Survival

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: August 3, 2021)

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

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Evaluate Efficacy, Safety and Tolerability, PK and PD of Emapalumab in Children and Adults With MAS in Still's or SLE
• Official Title: 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
• Brief Summary: 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.

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
• Study Phase: Phase 3

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

2 cohorts

Masking: None (Open Label)
Masking Description:

Open label

Primary Purpose: Treatment

Condition

• Macrophage Activation Syndrome
• Secondary Hemophagocytic Lymphohistiocytosis
• Still Disease
• Systemic Lupus Erythematosus
• SJIA
• AOSD
• MAS

Intervention

Drug: Emapalumab

Emapalumab iv infusion

Other Names:

• NI-0501
• emapalumab-lzsg
• ATC code: L04AA39 (WHO)

Study Arms

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

Intervention: Drug: Emapalumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 3, 2021): 41
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2025
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 80 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Adnan Mahmood, MD; +46730983984; Adnan.Mahmood@sobi.com

Contact: Anna Westerdahl; Anna.Westerdahl@sobi.com

• Listed Location Countries: Belgium, Canada, China, Czechia, France, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT05001737
• Other Study ID Numbers: NI-0501-14; 2021-001577-24 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Swedish Orphan Biovitrum
• Original Responsible Party: Same as current
• Current Study Sponsor: Swedish Orphan Biovitrum
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Radmila Kanceva, MD; Swedish Orphan Biovitrum

• PRS Account: Swedish Orphan Biovitrum
• Verification Date: April 2023