Clinical trial NCT05001737: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Macrophage Activation Syndrome
Secondary Hemophagocytic Lymphohistiocytosis
Still Disease
Systemic Lupus Erythematosus
SJIA
AOSD
MAS
Lead sponsor: Swedish Orphan Biovitrum
Sponsor class: INDUSTRY
First posted: 2021-08-12
Enrollment: 33
Sex: ALL
Minimum age (years): 6
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 2 cohorts
Primary purpose: TREATMENT

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)

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.

Primary outcomes:
measure: Proportion of subjects with complete response (CR) at Week 8 after first administration of emapalumab
timeFrame: 8 weeks
Secondary outcomes:
measure: 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
timeFrame: At any time in the study, up to 1 year
measure: GCs tapering to ≤1mg/kg/day of PDN equivalent at any time during the study.
timeFrame: At any time in the study, up to 1 year
measure: Time to achieve GCs tapering as defined above.
timeFrame: At any time in the study, up to 1 year
measure: Time to first Complete Remission
timeFrame: At any time in the study, up to 1 year
measure: Proportion of subjects with overall response as defined by CR or PR
timeFrame: At any time in the study, up to 1 year
measure: Time to first overall response as defined by CR or PR
timeFrame: At any time in the study, up to 1 year
measure: MAS recurrence at anytime after achievement of CR
timeFrame: At any time after CR, up to 1 year
measure: Withdrawal from the study due to lack of response as per Investigator decision
timeFrame: At any time in the study, up to 1 year
measure: Survival time
timeFrame: At any time in the study, up to 1 year
Other outcomes:
measure: Adverse Events (AEs) (serious and non-serious).
timeFrame: At any time in the study, up to 1 year
measure: Study interruption due to safety reasons
timeFrame: At any time in the study, up to 1 year
measure: Laboratory parameters
timeFrame: At any time in the study, up to 1 year
measure: Patient reported outcomes : PedsQL™;
timeFrame: Screening, Week 8, month 6 and 1 year
measure: Patient reported outcomes: Patient/Parent Global Impression of Severity
timeFrame: Screening, Week 8, month 6 and 1 year
measure: Patient reported outcomes: Clinician Global Impression of Severity
timeFrame: Screening, Week 8, month 6 and 1 year
measure: PK endpoints
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PK endpoints CEOI,
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PK endpoints: λz,
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PK endpoints: CL,
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PK endpoints: Vss,
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PK endpoints: MRTlast and MRTinf
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PD endpoints per cohort: free IFN-γ and total IFNγ
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PD endpoints per cohort: chemokines
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: PD endpoints per cohort: sCD25)
timeFrame: Every treatment visit until week 8, Day 60, Day 100, 6 months, 1 year
measure: Immunogenicity endpoints
timeFrame: Treatment visit 1, week 8, 6 months, 1 year
Locations:
city: Birmingham
country: United States
facility: UAB Hospital
state: Alabama
city: Los Angeles
country: United States
facility: UCLA Health
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Minneapolis
country: United States
facility: University of Minnesota Masonic Children's Hospital
state: Minnesota
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital, Abigail Wexner Research Institute
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Calgary
country: Canada
facility: Alberta Children's Hospital
city: Calgary
country: Canada
facility: University of Calgary
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
city: Toronto
country: Canada
facility: Hospital for sick children
city: Beijing
country: China
facility: Beijing Children's Hospital
city: Beijing
country: China
facility: Beijing Friendship Hospital
city: Shanghai
country: China
facility: Children's Hospital of Fudan University
city: Olomouc
country: Czechia
facility: Fakultní nemocnice Olomouc
city: Praha
country: Czechia
facility: Vseobecna Fakultni Nemocnice v Praze
city: Lille
country: France
facility: Hôpital Claude Huriez
city: Marseille
country: France
facility: Hôpital De La Conception
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
city: Paris
country: France
facility: Hôpital Universitaire Pitié Salpêtrière
city: Berlin
country: Germany
facility: Charité Universitätsmedizin
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Genova
country: Italy
facility: IRCCS G. Gaslini
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Trieste
country: Italy
facility: IRCCS - Materno-Infantile Burlo Garofolo
city: Kawasaki
country: Japan
facility: St. Marianna University School of Medicine Hospital
city: Takatsuki
country: Japan
facility: Osaka Medical and Pharmaceutical University Hospital
city: Tokyo
country: Japan
facility: Tokyo Medical and Dental University Hospital
city: Yokohama
country: Japan
facility: Yokohama City University Hospital
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Kraków
country: Poland
facility: Szpital Specjalistyczny im. J. Dietla w Krakowie
city: Kraków
country: Poland
facility: Wojewódzki Specjalistyczny Szpital Dziecięcy im. św. Ludwika w Krakowie
city: Poznań
country: Poland
facility: Ortopedyczno - Rehabilitacyjny Szpital Kliniczny im. Wiktora Degi Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu
city: La Paz
country: Spain
facility: Hospital Universitario La Paz
city: La Paz
country: Spain
facility: Hospital Universitario
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
Study officials:
affiliation: Swedish Orphan Biovitrum
name: Brian Jamieson, MD
role: STUDY_DIRECTOR
References: