Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile, Adult Onset Still Disease
Conditions
Keywords
Emapalumab, Gamifant, Macrophage activation syndrome, Secondary hemophagocytic lymphohistiocytosis, Interferon-gamma, Systemic juvenile idiopathic arthritis, Adult-onset Still's disease, MAS, HLH, sHLH, IFN-gamma, IFNγ, sJIA, AOSD, NI-0501-06, NI-0501
Brief summary
Macrophage Activation Syndrome (MAS) is a rare, life-threatening condition characterized by uncontrolled hyperinflammation which may develop on the background of systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD). Emapalumab is a monoclonal antibody neutralizing interferon-gamma (IFN-gamma), a key cytokine which contributes to the inflammation and tissue damage seen in MAS. The purpose of this study is to assess the safety, tolerability and efficacy of emapalumab in sJIA or AOSD participants developing MAS, presenting an inadequate response to high dose glucocorticoid treatment.
Interventions
DRUGEmapalumab
Emapalumab was administered at an initial dose of 6 mg/kg by intravenous infusion. Emapalumab treatment continued at a dose of 3 mg/kg, every 3 days until study day 15, and then twice-a-week for an additional 2 weeks, i.e., until study day 28. The emapalumab regimen could be adapted (the frequency between infusions shortened, the dose increased, or the treatment prolonged beyond 4 weeks) upon assessment of a favourable benefit-risk profile. There was a 4-week off-drug follow-up period (up to Week 8).
Sponsors
Swedish Orphan Biovitrum
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients of both genders * For sJIA patients: Confirmed sJIA diagnosis. For patients presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility. For AOSD patients: confirmed AOSD diagnosis as per Yamaguchi criteria. * Diagnosis of active MAS. * An inadequate response to high dose i.v. glucocorticoid treatment administered for at least 3 days as per local standard of care (including but not limited to pulses of 30 mg/kg PDN on 3 consecutive days). High dose i.v. glucocorticoid should not be lower than 2 mg/kg/day of PDN equivalent in 2 divided doses (or at least 60 mg/day in patients of 30 kg or more). In case of rapid worsening of the patient's condition and/or lab parameters, inclusion may occur within less than 3 days from starting high dose i.v. glucocorticoids. * Tocilizumab, TNF inhibitors and canakinumab, if administered, have to be discontinued before emapalumab initiation. * Having received guidance on contraception for both male and female patients sexually active and having reached puberty. Females of child-bearing potential require use of highly effective contraceptive measures. Males with partners(s) of child-bearing potential must agree to take appropriate precautions. * Informed consent provided by the patient (as required by local law), or by the patient's legally authorized representative(s) with the assent of patients who are legally capable of providing it, as applicable.
Exclusion criteria
* Diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease. * Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections. * Clinical suspicion of latent tuberculosis. * Positive serology for HIV antibodies. * Presence of malignancy. * Patients who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, CNS, liver or renal function that in the opinion of the Investigator may significantly affect likelihood to respond to treatment and/or assessment of emapalumab safety. * History of hypersensitivity or allergy to any component of the study drug * Receipt of a BCG vaccine within 12 weeks prior to screening. * Receipt of live or attenuated live vaccines (other than BCG) within 6 weeks prior to screening. * Pregnant or lactating female patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Up to Week 8 | — |
| Evolution of Laboratory Parameters | Up to Week 8 | Shifts from baseline in the following MAS-relevant laboratory parameters are reported: * Leukocytes * Platelets * Lactate dehydrogenase (LDH) * Alanine aminotransferase (ALT) * Aspartate aminotransferase (AST) * Ferritin * C-reactive protein * Activated partial thromboplastin time (aPTT) * Prothrombin time * D-dimer * Fibrinogen |
| Number of Participants Withdrawn Due to Safety Reasons | Up to Week 8 | — |
| Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment | Week 8 | Remission from MAS was evaluated according to the following criteria: Resolution of clinical signs and symptoms according to the investigator (MAS clinical signs and symptoms activity score ≤ 1) and Normalization of laboratory parameters relevant to MAS, as follows: * WBC count and platelet count above the LLN. * LDH below 1.5 × the ULN. * ALT and AST both below 1.5 × the ULN. * Fibrinogen higher than 100 mg/dL. * Ferritin levels decreased by at least 80 % from values at screening or baseline (whichever was higher) or below 2000 ng/mL, whichever was lower. |
| Time to First MAS Remission | Up to Week 8 | — |
| Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study | Up to Week 8 | Permanently tapering by at least 50% of the equivalent dose of prednisone. This was defined as achieving reduction of 50% of the baseline dose \[SD0\] and maintaining the reduction until the end of study). |
| Time to Achievement of Permanent Glucocorticoids Tapering | Up to Week 8 | Time to achievement of permanent glucocorticoid tapering by at least 50% of the equivalent dose of prednisone administered at emapalumab treatment start. |
| Survival Time | Up to Week 8 | Number of participants alive at the end of the study |
| Number of Participants Withdrawn From the Study Due to Lack of Efficacy | Up to Week 8 | Number of participants withdrawn from the study due to lack of efficacy |
| Levels of Emapalumab Concentration | Data from the following time points are presented: SD0 (pre- and post-dose), Week 4 Visit 2 (pre- and post-dose), and 4-week follow-up visit/EoS. | On all infusion days, PK samples were collected before the infusion start and between 15 and 30 minutes after infusion completion. In addition, following the first emapalumab infusion, PK samples were collected approximately 24 and 48 hours post-infusion, and following the second emapalumab infusion, PK samples were collected approximately 48 hours post-infusion. Upon treatment completion, PK samples were collected on all non-infusion visits until the 4-week follow-up visit/EOS. |
| Pharmacodynamic Parameters | Up to Week 8 | Levels of total INF-gamma, CXCL9 and CXCL10 |
| Number of Participants Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity | Up to Week 8 | The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs). |
Countries
France, Italy, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants Baseline data are provided for all participants who were enrolled in the study. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | All Enrolled Participants |
|---|---|
| Age, Categorical <=18 years | 13 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 9.9 years STANDARD_DEVIATION 6.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 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 | 1 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment France | 1 Participants |
| Region of Enrollment Italy | 7 Participants |
| Region of Enrollment Spain | 1 Participants |
| Region of Enrollment United Kingdom | 2 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 13 / 14 |
| serious Total, serious adverse events | 6 / 14 |
Outcome results
Primary
Evolution of Laboratory Parameters
Shifts from baseline in the following MAS-relevant laboratory parameters are reported: * Leukocytes * Platelets * Lactate dehydrogenase (LDH) * Alanine aminotransferase (ALT) * Aspartate aminotransferase (AST) * Ferritin * C-reactive protein * Activated partial thromboplastin time (aPTT) * Prothrombin time * D-dimer * Fibrinogen
Time frame: Up to Week 8
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Treated Population | Evolution of Laboratory Parameters | Leukocytes: From a high value at baseline to a value within the reference range at Week 8 | 2 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Leukocytes: From a low value at baseline to a value within the reference range at Week 8 | 4 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Leukocytes: From a low value at baseline to a high value at Week 8 | 2 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Platelets: From a high value at baseline to a value within the reference range at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Platelets: From a low value at baseline to a value within the reference range at Week 8 | 6 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Platelets: From a low value at baseline to a high value at Week 8 | 3 Participants |
| All Treated Population | Evolution of Laboratory Parameters | LDH: From a high value at baseline to a value within the reference range at Week 8 | 6 Participants |
| All Treated Population | Evolution of Laboratory Parameters | ALT: From a high value at baseline to a value within the reference range at Week 8 | 10 Participants |
| All Treated Population | Evolution of Laboratory Parameters | ALT: From a high value at baseline to a low value at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | AST: From a high value at baseline to a value within the reference range at Week 8 | 11 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Ferritin: From a high value at baseline to a value within the reference range at Week 8 | 11 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Ferritin: From a high value at baseline to a low value at Week 8 | 2 Participants |
| All Treated Population | Evolution of Laboratory Parameters | C-reactive protein: From a high value at baseline to a value within the reference range at Week 8 | 9 Participants |
| All Treated Population | Evolution of Laboratory Parameters | aPTT: From a high value at baseline to a value within the reference range at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | aPTT: From a high value at baseline to a low value at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | aPTT: From a value within the reference range at baseline to a low value at Week 8 | 3 Participants |
| All Treated Population | Evolution of Laboratory Parameters | aPTT: From a low value at baseline to a value within the reference range at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | aPTT: From a low value at baseline to a high value at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Prothrombin time: From a high value at baseline to a value within the reference range at Week 8 | 5 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Prothrombin time: From a high value at baseline to a low value at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Prothrombin time: From a value within the reference range at baseline to a low value at Week 8 | 3 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Prothrombin time: From a low value at baseline to a value within the reference range at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | D-dimer: From a high value at baseline to a value within the reference range at Week 8 | 8 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Fibrinogen: From a high value at baseline to a value within the reference range at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Fibrinogen: From a value within the reference range at baseline to a high value at Week 8 | 1 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Fibrinogen: From a low value at baseline to a value within the reference range at Week 8 | 5 Participants |
| All Treated Population | Evolution of Laboratory Parameters | Fibrinogen: From a low value at baseline to a high value at Week 8 | 1 Participants |
Primary
Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious)
Time frame: Up to Week 8
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a TEAE with an outcome of unknown | 1 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a TEAE | 13 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a serious TEAE | 6 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a severe TEAE | 2 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a moderate TEAE | 10 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a mild TEAE | 13 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a TEAE related to emapalumab | 4 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a TEAE unrelated to emapalumab | 13 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a TEAE with an outcome of recovered/resolved | 13 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a TEAE with an outcome of not recovered/not resolved | 3 Participants |
| All Treated Population | Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) | Number of participants with a TEAE with an outcome of recovering/resolving | 1 Participants |
Primary
Levels of Emapalumab Concentration
On all infusion days, PK samples were collected before the infusion start and between 15 and 30 minutes after infusion completion. In addition, following the first emapalumab infusion, PK samples were collected approximately 24 and 48 hours post-infusion, and following the second emapalumab infusion, PK samples were collected approximately 48 hours post-infusion. Upon treatment completion, PK samples were collected on all non-infusion visits until the 4-week follow-up visit/EOS.
Time frame: Data from the following time points are presented: SD0 (pre- and post-dose), Week 4 Visit 2 (pre- and post-dose), and 4-week follow-up visit/EoS.
Population: Emapalumab concentrations were below the detection limit for all patients at SD0, except for Patient 501-001, in whom the emapalumab concentration (pre-dose) was 62108.4 μg/L. It should be noted that on SD1, the measurement results of emapalumab were below the detection limit for Patient 501-001, so it could not be ruled out that the samples from SD0 and SD1 for this patient were interchanged.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Treated Population | Levels of Emapalumab Concentration | Study Day 0 (pre-dose) | 5455.444 μg/L | Standard Deviation 19985.066 |
| All Treated Population | Levels of Emapalumab Concentration | Study Day 0 (post-dose) | 104740.254 μg/L | Standard Deviation 20994.1054 |
| All Treated Population | Levels of Emapalumab Concentration | Week 4 Visit 2 (pre-dose) | 115472.076 μg/L | Standard Deviation 58676.7953 |
| All Treated Population | Levels of Emapalumab Concentration | Week 4 Visit 2 (post-dose) | 212900.657 μg/L | Standard Deviation 87466.3031 |
| All Treated Population | Levels of Emapalumab Concentration | 4-week follow-up Visit/EoS | 46447.462 μg/L | Standard Deviation 33657.0174 |
Primary
Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment
Remission from MAS was evaluated according to the following criteria: Resolution of clinical signs and symptoms according to the investigator (MAS clinical signs and symptoms activity score ≤ 1) and Normalization of laboratory parameters relevant to MAS, as follows: * WBC count and platelet count above the LLN. * LDH below 1.5 × the ULN. * ALT and AST both below 1.5 × the ULN. * Fibrinogen higher than 100 mg/dL. * Ferritin levels decreased by at least 80 % from values at screening or baseline (whichever was higher) or below 2000 ng/mL, whichever was lower.
Time frame: Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Treated Population | Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment | 11 Participants |
Primary
Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study
Permanently tapering by at least 50% of the equivalent dose of prednisone. This was defined as achieving reduction of 50% of the baseline dose \[SD0\] and maintaining the reduction until the end of study).
Time frame: Up to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Treated Population | Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study | 12 Participants |
Primary
Number of Participants Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity
The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).
Time frame: Up to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Treated Population | Number of Participants Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity | 0 Participants |
Primary
Number of Participants Withdrawn Due to Safety Reasons
Time frame: Up to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Treated Population | Number of Participants Withdrawn Due to Safety Reasons | 0 Participants |
Primary
Number of Participants Withdrawn From the Study Due to Lack of Efficacy
Number of participants withdrawn from the study due to lack of efficacy
Time frame: Up to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Treated Population | Number of Participants Withdrawn From the Study Due to Lack of Efficacy | 0 Participants |
Primary
Pharmacodynamic Parameters
Levels of total INF-gamma, CXCL9 and CXCL10
Time frame: Up to Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Treated Population | Pharmacodynamic Parameters | CXCL9 | 21986.010 ng/L | Standard Deviation 29405.8787 |
| All Treated Population | Pharmacodynamic Parameters | CXCL10 | 7935.418 ng/L | Standard Deviation 9115.2857 |
| All Treated Population | Pharmacodynamic Parameters | Total IFN-γ | 425.528 ng/L | Standard Deviation 1191.8391 |
| All Treated Population: 4-week Follow-up Visit/EoS | Pharmacodynamic Parameters | CXCL9 | 255.654 ng/L | Standard Deviation 596.4149 |
| All Treated Population: 4-week Follow-up Visit/EoS | Pharmacodynamic Parameters | CXCL10 | 639.102 ng/L | Standard Deviation 1058.9589 |
| All Treated Population: 4-week Follow-up Visit/EoS | Pharmacodynamic Parameters | Total IFN-γ | 2132.656 ng/L | Standard Deviation 2967.492 |
Primary
Survival Time
Number of participants alive at the end of the study
Time frame: Up to Week 8
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Treated Population | Survival Time | 14 Participants |
Primary
Time to Achievement of Permanent Glucocorticoids Tapering
Time to achievement of permanent glucocorticoid tapering by at least 50% of the equivalent dose of prednisone administered at emapalumab treatment start.
Time frame: Up to Week 8
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Treated Population | Time to Achievement of Permanent Glucocorticoids Tapering | 14.5 days |
Primary
Time to First MAS Remission
Time frame: Up to Week 8
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Treated Population | Time to First MAS Remission | 25 days |