Macrophage Activation Syndrome, Secondary Hemophagocytic Lymphohistiocytosis, Still Disease, Systemic Lupus Erythematosus, SJIA, AOSD, MAS
Conditions
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)
Interventions
DRUGEmapalumab
Emapalumab iv infusion
Sponsors
Swedish Orphan Biovitrum
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label
Intervention model description
2 cohorts
Eligibility
Sex/Gender
ALL
Age
6 Months to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Complete Response (CR) at Week 8 After First Administration of Emapalumab | 8 weeks | Resolution of clinical signs and symptoms present at baseline: The macrophage activation syndrome (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 lower |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Glucocorticoids (GC)s 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 | At any time within the first 8 weeks from start of emapalumab treatment | GC tapering as per investigator discretion |
| Number of Patients With GCs Tapering to ≤1mg/kg/Day of PDN Equivalent at Any Time Until End of Study (EOS). | At any time in the study, up to 1 year | GC tapering as per investigator discretion |
| Time to Achieve GCs Tapering | At any time in the study, up to 1 year | Median time to achieve GCs tapering to a dose \< 50 % of PDN equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of MAS (in patients already treated for the underlying condition), or to ≤1mg/kg/Day of PDN Equivalent, whichever occurs first at any time during the study GC tapering as per investigator discretion |
| Time to First Complete Response (CR) | At any time in the study, up to 1 year | Time to CR until EOS Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity was measured on a visual analog scale (VAS) 10 cm. Definition of CR: Resolution of clinical signs and symptoms present at baseline: MAS clinical activity was measured on a 10-cm VAS. Clinical signs were considered resolved if VAS was below or equal to 1/10. and Normalization of laboratory parameters relevant to MAS as follows: * WBC \>LLN. * Platelet count \>LLN. * LDH \<1.5 ULN. * ALT \<1.5 ULN. * AST \<1.5 ULN. * Fibrinogen \>100 mg/dL. * Ferritin levels decreased by at least 80% from values at Screening or baseline (whichever was higher) or \<2000 ng/mL, whichever was lower. |
| Proportion of Subjects With Overall Response as Defined by CR or Partial Response (PR) | At week 8 | Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity was measured on a visual analog scale (VAS) 10 cm. CR: Resolution of clinical signs and symptoms present at baseline: MAS clinical activity was measured on a 10-cm VAS. Clinical signs were considered resolved if VAS was below or equal to 1/10. and Normalization of laboratory parameters relevant to MAS as follows: * WBC \>LLN. * Platelet count \>LLN. * LDH \<1.5 ULN. * ALT \<1.5 ULN. * AST \<1.5 ULN. * Fibrinogen \>100 mg/dL. * Ferritin levels decreased by at least 80% from values at Screening or baseline (whichever was higher) or \<2000 ng/mL, whichever was lower. PR: Resolution or improvement in clinical signs and symptoms measured by the MAS clinical activity on the VAS. The patient was classified as PR if he or she presented a VAS \<4/10. and Normalization of at least 3 of the abnormal baseline laboratory parameters relevant to MAS, as defined above. |
| Time to First Overall Response as Defined by CR or PR | At any time in the study, up to 1 year | Time to first overall response CR: Resolution of clinical signs and symptoms present at baseline: MAS clinical activity was measured on a 10-cm VAS. Clinical signs were considered resolved if VAS was below or equal to 1/10. and Normalization of laboratory parameters relevant to MAS as follows: * WBC \>LLN. * Platelet count \>LLN. * LDH \<1.5 ULN. * ALT \<1.5 ULN. * AST \<1.5 ULN. * Fibrinogen \>100 mg/dL. * Ferritin levels decreased by at least 80% from values at Screening or baseline (whichever was higher) or \<2000 ng/mL, whichever was lower. PR: Resolution or improvement in clinical signs and symptoms measured by the MAS clinical activity on the VAS. The patient was classified as PR if he or she presented a VAS \<4/10. and Normalization of at least 3 of the abnormal baseline laboratory parameters relevant to MAS, as defined above. |
| MAS Recurrence at Anytime After Achievement of CR | At any time after CR, up to 1 year | Number of patients with MAS recurrence at anytime after achievement of CR |
| Withdrawal From the Study Due to Lack of Response | At any time in the study, up to 1 year | Number of patients withdrawn from the study due to lack of response as per Investigator decision |
| Survival | At end of study, 1 year | Number of patients alive at the end of study |
Countries
Belgium, Canada, China, Czechia, France, Germany, Italy, Japan, Netherlands, Poland, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORBrian Jamieson, MD
Swedish Orphan Biovitrum
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 4 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 15.5 years STANDARD_DEVIATION 13.83 |
| Body weight | 44.48 kg STANDARD_DEVIATION 21.777 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment Belgium | 1 participants |
| Region of Enrollment Canada | 2 participants |
| Region of Enrollment China | 1 participants |
| Region of Enrollment Czechia | 4 participants |
| Region of Enrollment France | 2 participants |
| Region of Enrollment Germany | 2 participants |
| Region of Enrollment Italy | 4 participants |
| Region of Enrollment Japan | 2 participants |
| Region of Enrollment Netherlands | 2 participants |
| Region of Enrollment Spain | 3 participants |
| Region of Enrollment United Kingdom | 2 participants |
| Region of Enrollment United States | 4 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 25 | 0 / 8 |
| other Total, other adverse events | 24 / 25 | 8 / 8 |
| serious Total, serious adverse events | 18 / 25 | 4 / 8 |
Outcome results
None listed