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

Systemic Lupus Erythematosus Clinical Trial

— EMERALD  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05001737
• Other study ID #: NI-0501-14
• Secondary ID: 2021-001577-24
• Status: Recruiting
• Phase: Phase 3
• Start date: December 15, 2021
• Est. completion date: September 2025

Study information

• Verified date: February 2024
• Source: Swedish Orphan Biovitrum
• Contact: Adnan Mahmood, MD
• Phone: +46(0)8 697 20 00
• Email: Adnan.Mahmood[@]sobi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 41
• Est. completion date: September 2025
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Lymphohistiocytosis, Hemophagocytic
• Macrophage Activation Syndrome
• Systemic Lupus Erythematosus

Intervention

Drug:
• Emapalumab
Emapalumab iv infusion

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Leuven	Leuven
Canada	Alberta Children's Hospital	Calgary
Canada	University of Calgary	Calgary
Canada	Centre Hospitalier de l'Université de Montréal	Montréal
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montréal
Canada	Hospital for sick children	Toronto
China	Beijing Children's Hospital	Beijing
China	Beijing Friendship Hospital	Beijing
China	Children's Hospital of Fudan University	Shanghai
Czechia	Fakultní nemocnice Olomouc	Olomouc
Czechia	Vseobecna Fakultni Nemocnice v Praze	Praha
France	Hôpital Claude Huriez	Lille
France	Hôpital De La Conception	Marseille
France	Hôpital Necker-Enfants Malades	Paris
France	Hôpital Universitaire Pitié Salpêtrière	Paris
Germany	Charité Universitätsmedizin	Berlin
Germany	Universitätsklinikum Heidelberg	Heidelberg
Italy	IRCCS G. Gaslini	Genova
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	Ospedale Pediatrico Bambino Gesù	Roma
Italy	IRCCS - Materno-Infantile Burlo Garofolo	Trieste
Japan	St. Marianna University School of Medicine Hospital	Kawasaki
Japan	Osaka Medical and Pharmaceutical University Hospital	Takatsuki
Japan	Tokyo Medical and Dental University Hospital	Tokyo
Japan	Yokohama City University Hospital	Yokohama
Netherlands	UMC Utrecht	Utrecht
Poland	Szpital Specjalistyczny im. J. Dietla w Krakowie	Kraków
Poland	Wojewódzki Specjalistyczny Szpital Dzieciecy im. sw. Ludwika w Krakowie	Kraków
Poland	Ortopedyczno - Rehabilitacyjny Szpital Kliniczny im. Wiktora Degi Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Poznan
Spain	Hospital Sant Joan de Déu	Barcelona
Spain	Hospital Universitario	La Paz
Spain	Hospital Universitario La Paz	La Paz
Spain	Hospital Universitari i Politècnic La Fe	Valencia
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm
Sweden	Karolinska Universitetssjukhuset Solna (Ped. Rheum.)	Stockholm
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	Imperial College Healthcare NHS Trust	London
United States	Akron Children's Hospital	Akron	Ohio
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	UAB Hospital	Birmingham	Alabama
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hospital, Abigail Wexner Research Institute	Columbus	Ohio
United States	University of Florida	Gainesville	Florida
United States	UCLA Health	Los Angeles	California
United States	University of Minnesota Masonic Children's Hospital	Minneapolis	Minnesota
United States	UPMC Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Rheumatology Clinic at University of Washington Medical Center - Roosevelt	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Swedish Orphan Biovitrum

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  China,  Czechia,  France,  Germany,  Italy,  Japan,  Netherlands,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Events (AEs) (serious and non-serious).	Incidence, severity, causality and outcomes of AEs	At any time in the study, up to 1 year
Other	Study interruption due to safety reasons	Number of subjects withdrawn due to safety reasons	At any time in the study, up to 1 year
Other	Laboratory parameters	Changes from baseline	At any time in the study, up to 1 year
Other	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
Other	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
Other	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
Other	PK endpoints	Serum concentrations of emapalumab vs. time	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	PK endpoints CEOI,	PK parameters by non-compartmental analysis: CEOI,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	PK endpoints: ?z,	PK parameters by non-compartmental analysis: ?z,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	PK endpoints: CL,	PK parameters by non-compartmental analysis: CL,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	PK endpoints: Vss,	PK parameters by non-compartmental analysis: Vss,	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	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
Other	PD endpoints per cohort: free IFN-? and total IFN?	• Levels of circulating free IFN-? at pre-dose, and total IFN? (free IFN-?+bound to emapalumab) after initiation of the study drug.	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	PD endpoints per cohort: chemokines	Levels of the main IFN-?-induced chemokines (CXCL9, CXCL10).	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	PD endpoints per cohort: sCD25)	Levels of MAS markers (sCD25).	Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
Other	Immunogenicity endpoints	Occurrence of ADAs, Nab to emapalumab	Treatment visit 1, week 8, 6 months, 1 year
Primary	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	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
Secondary	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
Secondary	Time to achieve GCs tapering as defined above.	GC tapering as per investigator discretion	At any time in the study, up to 1 year
Secondary	Time to first Complete Remission	Time to CR	At any time in the study, up to 1 year
Secondary	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
Secondary	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
Secondary	MAS recurrence at anytime after achievement of CR	Time to MAS recurrence after CR	At any time after CR, up to 1 year
Secondary	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
Secondary	Survival time	Time to Survival	At any time in the study, up to 1 year