Macrophage Activation SyndromePhase 2NCT03311854
A Study to Investigate the Safety and Efficacy of Emapalumab, an Anti-IFN-gamma mAb in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
A Phase 2 study testing Emapalumab in people with Macrophage Activation Syndrome and Lymphohistiocytosis, Hemophagocytic, run by Swedish Orphan Biovitrum at 5 sites in 5 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 0 years and older
- Conditions the study is for
- Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile
- What is being tested?
- Emapalumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 5 sitesin 5 countries
- Study dates
- 20 Feb 2018to 19 May 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 10Show fewer
- 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.
Trial locations and contacts
5 sites in 5 countries.
5 sites in 5 countries
United States1 site
Cincinnati Children'S Hospital
Cincinnati, Ohio, 45229
France1 site
Hôpital Necker-Enfants Malades, Unité d'Immunologie-hématologie et Rhumatologie pédiatriques
Paris, 75743
United Kingdom1 site
Great Ormond Street Hospital for Children
London, WC1N 3JH
About this study
Official title: A Pilot, Open-label, Single Arm, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Administrations of Emapalumab, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
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.
- Conditions
- Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile, Adult Onset Still Disease
- Being tested
- Emapalumab
- 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
- Medical subject headings
- Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile, Still's Disease, Adult-Onset
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EmapalumabDrug
Also called Gamifant
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).
| Study group | Role | What they receive |
|---|---|---|
| Emapalumab | Experimental | Not described Receives: Drug: Emapalumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious)
Measured: Up to Week 8
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
Measured: Up to Week 8
Number of Participants Withdrawn Due to Safety Reasons
Measured: Up to Week 8
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.
Measured: Week 8
Time to First MAS Remission
Measured: Up to Week 8
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).
Measured: Up to Week 8
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.
Measured: Up to Week 8
Survival Time
Number of participants alive at the end of the study
Measured: Up to Week 8
Number of Participants Withdrawn From the Study Due to Lack of Efficacy
Number of participants withdrawn from the study due to lack of efficacy
Measured: Up to Week 8
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.
Measured: 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.
Pharmacodynamic Parameters
Levels of total INF-gamma, CXCL9 and CXCL10
Measured: Up to Week 8
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).
Measured: Up to Week 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Oct 2017
- Study start20 Feb 2018
- Primary completion19 May 2020
- Study completion19 May 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Macrophage Activation SyndromeStudies of the same condition, open and under way.
- More trials run by Swedish Orphan BiovitrumThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- Swedish Orphan Biovitrum
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03311854
- Sponsor's protocol ID
- NI-0501-06
- Status last verified
- May 2022
- First submitted
- 21 Aug 2017
- Last updated
- 17 May 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Brossard P, Laveille C. Population Pharmacokinetics of the Anti-Interferon-Gamma Monoclonal Antibody Emapalumab: An Updated Analysis. Rheumatol Ther. 2024 Jun;11(3):869-880. doi: 10.1007/s40744-024-00669-y. Epub 2024 Apr 25.
PubMed 38662147De Benedetti F, Grom AA, Brogan PA, Bracaglia C, Pardeo M, Marucci G, Eleftheriou D, Papadopoulou C, Schulert GS, Quartier P, Anton J, Laveille C, Frederiksen R, Asnaghi V, Ballabio M, Jacqmin P, de Min C. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis. 2023 Jun;82(6):857-865. doi: 10.1136/ard-2022-223739. Epub 2023 Mar 31.
PubMed 37001971
Study at a glance
From the registry record, last updated by the sponsor on 17 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot, Open-label, Single Arm, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Administrations of Emapalumab, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
- ClinicalTrials.gov ID
- NCT03311854
- Acronym / sponsor ID
- NI-0501-06
- Conditions
- Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile, Adult Onset Still Disease
- Keywords
- Emapalumab, Gamifant, Macrophage activation syndrome, Secondary hemophagocytic lymphohistiocytosis, Interferon-gamma, Systemic juvenile idiopathic arthritis, Adult-onset Still's disease, MAS
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Swedish Orphan BiovitrumIndustry (pharma, biotech, devices)
- Study start
- 20 Feb 2018 (actual)
- Primary completion
- 19 May 2020 (actual)
- Study completion
- 19 May 2020 (actual)
- First posted
- 17 Oct 2017 (actual)
- Results
- Posted 26 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Emapalumab | Experimental | Drug: Emapalumab |
Who may qualify
- Ages
- 0 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EmapalumabAlso: GamifantEmapalumab 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). | Drug | Emapalumab |
Primary outcome
Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious)
Time frame: Up to Week 8
Evolution of Laboratory Parameters
Time frame: 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
Time frame: Up to Week 8
Number of Participants Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment
Time frame: 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
Time frame: Up to Week 8
Number of Participants for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Up to Week 8
Number of participants withdrawn from the study due to lack of efficacy
Levels of Emapalumab Concentration
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.
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
Time frame: 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
Time frame: Up to Week 8
The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 May 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38662147Brossard P, Laveille C. Population Pharmacokinetics of the Anti-Interferon-Gamma Monoclonal Antibody Emapalumab: An Updated Analysis. Rheumatol Ther. 2024 Jun;11(3):869-880. doi: 10.1007/s40744-024-00669-y. Epub 2024 Apr 25.
- Derived from this study: PubMed 37001971De Benedetti F, Grom AA, Brogan PA, Bracaglia C, Pardeo M, Marucci G, Eleftheriou D, Papadopoulou C, Schulert GS, Quartier P, Anton J, Laveille C, Frederiksen R, Asnaghi V, Ballabio M, Jacqmin P, de Min C. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis. 2023 Jun;82(6):857-865. doi: 10.1136/ard-2022-223739. Epub 2023 Mar 31.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
5 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Emapalumab in people with Macrophage Activation Syndrome and Lymphohistiocytosis, Hemophagocytic, run by Swedish Orphan Biovitrum at 5 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 May 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States, France, Italy, Spain, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence, Severity, Causality, and Outcomes of AEs (Serious and Nonserious) (time frame: Up to Week 8). The study lists 12 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03311854, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 May 2022.