A study to evaluate efficacy, safety and tolerability, pharmacokinetics and pharmacodynamics of emapalumab in children and adults with macrophage activation syndrome (MAS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Swedish Orphan Biovitrum AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

28 Mar 2022 → 4 Jun 2025

Decision date (initial)

2024-09-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Swedish Orphan Biovitrum AG (Sobi AG)

External identifiers

EU CT number

2024-516153-52-00

EudraCT number

2021-001577-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacogenetic, Safety, Therapy, Pharmacodynamic

To demonstrate efficacy of emapalumab in the treatment of patients in:
- Cohort 1: Macrophage Activation Syndrome (MAS) in the context of
systemic juvenile idiopathic arthritis and adult onset Still's disease
(AOSD).
- Cohort 2: MAS in the context of pediatric and adult systemic lupus
erythematosus (SLE)

Secondary objectives 10

1. To demonstrate efficacy of emapalumab with respect to tapering of glucocorticoids (GCs).
2. To evaluate the time to onset of response to emapalumab treatment.
3. To evaluate efficacy of emapalumab with respect to overall response (OR).
4. To evaluate the sustained efficacy of emapalumab treatment.
5. To evaluate the patient's survival after treatment with emapalumab.
6. To evaluate the safety and tolerability of emapalumab.
7. To evaluate patient-reported outcome of MAS in patients treated with emapalumab.
8. To determine the pharmacokinetic (PK) profile of emapalumab.
9. To determine the pharmacodynamic (PD) profile of emapalumab.
10. To determine the immunogenicity of emapalumab

Conditions and MedDRA coding

Macrophage activation syndrome (MAS) in the context of Systemic Juvenile Idiopathic Arthritis (sJIA) and Adult onset Still's disease (AOSD). MAS in the context of pediatric and adult Systemic Lupus Erythematosus (SLE).

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002031-PIP01-16

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Informed consent provided by the patient or by the patient's legally authorized representative(s) with the assent of patients who are legally capable of providing it, as required by local law. (Run-in phase in all cohorts)
2. Male and female patients aged between 6 months and 80 years of age at the time of diagnosis of active MAS. (Run-in phase in all cohorts)
3. MAS defined as per the criteria defined below for each cohort and requiring treatment with GCs as per standard of care. (Run-in phase in all cohorts)
4. Informed consent provided by the patient or by the patient's legally authorized representative(s) with the assent of patients who are legally capable of providing it, as as required by local law. (Interventional phase in all cohorts)
5. Male and female patients aged between 6 months and 80 years of age at the time of diagnosis of active MAS. (Interventional phase in all cohorts)
6. Patients 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 methylprednisolone (mPDN) 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 patients of 30 kg or more, and at least 1 g/day in adult MAS patients). In case of rapid worsening of the patient's condition and/or laboratory parameters, as per Investigator judgment, inclusion may occur within less than 3 days from starting high dose GCs. (Interventional phase in all cohorts)
7. Diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the followings (Interventional phase in all cohorts): a. Febrile patients presenting with ferritin > 684 ng/mL. b. and any 2 of: i. Platelet count ≤ 181 x109/L ii. Aspartate aminotransferase (AST)-level > 48 U/L iii. Triglycerides > 156 mg/dL iv. Fibrinogen level ≤ 360 mg/dL
8. Female patients of child-bearing potential (sexually or non-sexually active). Female patients who are sexually active must be willing to use highly effective methods of contraception from study drug initiation to 6 months after the last dose of study drug. (Interventional phase in all cohorts)
9. Cohort 1 (Specific inclusion criteria for Cohort 1 and Cohort 2): a. Confirmed sJIA diagnosis. For patients presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility. b. Confirmed diagnosis of AOSD as per Yamaguchi criteria (Yamaguchi et al. 1992)
10. Cohort 2 (Specific inclusion criteria for Cohort 1 and Cohort 2): a. Confirmed diagnosis of SLE as per Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria.
11. Sexually active female patients of childbearing potential are expected to use highly effective methods of contraception during dosing and for 6 months after last dose of study drug. Highly effective contraception methods include: • Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: o Oral. o Intravaginal. o Transdermal. • Progestogen-only hormonal contraception associated with inhibition of ovulation: o Oral. o Injectable. o Implantable. • Intra-uterine device. • Intra-uterine hormone-releasing system. • Bilateral tubal occlusion. • Vasectomised partner. • Sexual abstinence.

Exclusion criteria 14

1. Primary hemophagocytic lymphohistiocytosis (p-HLH) documented by either the presence of a known causative genetic mutation or abnormal perforin expression or CD107a degranulation assay as described with pHLH or by the presence of family history.
2. Confirmed malignancy. Note: patients 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, Janus kinase (JAK) inhibitors, Tumour necorsis factor (TNF) inhibitors and tocilizumab at the time of emapalumab initiation.
4. Ongoing treatment with anakinra at a dose above 4 mg/kg/ day at time of emapalumab initiation.
5. Patients treated with etoposide for MAS in the last 1 month.
6. Presence of any medical or psychological condition or laboratory result that in the opinion of the Investigator can interfere with the patient's ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with emapalumab.
7. Foreseeable inability to cooperate with given instructions or study procedures.
8. Clinically active mycobacteria (typical and atypical), Histoplasma Capsulatum, or Salmonella infections.
9. Evidence of leishmania infections.
10. Evidence of latent tuberculosis.
11. History of hypersensitivity or allergy to any component of the study drug.
12. Receipt of a Bacillus Calmette-Guerin (BCG) vaccine within 12 weeks prior to screening.
13. Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to screening.
14. Pregnancy or lactating female patients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients with complete response (CR) at Week 8 after first administration of emapalumab.

Secondary endpoints 9

1. GCs tapering to a dose < 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 (in patients already treated for the underlying condition) whichever occurs first at any time during the study.
2. GCs tapering to ≤ 1 mg/kg/day of PDN equivalent at any time during the study.
3. Time to achieve GCs tapering as defined in the 2 bullets above.
4. Time to first CR.
5. Proportion of patients with overall response (OR) as defined by CR or PR (partial response).
6. Time to first overall response (OR) as defined by CR or PR.
7. MAS recurrence at any time after achievement of CR.
8. Withdrawal from the study due to lack of response as per Investigator decision.
9. Survival time.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Swedish Orphan Biovitrum AG

Sponsor organisation

Swedish Orphan Biovitrum AG

Address

Messeplatz 10

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

Swedish Orphan Biovitrum AG

Contact name

Swedish Orphan Biovitrum AG (Sobi AG), Clinical Development Swedish Orphan

Public contact point

Organisation

Swedish Orphan Biovitrum AG

Contact name

Swedish Orphan Biovitrum AG (Sobi AG), Clinical Development Swedish Orphan

Third parties 9

Locations

3 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 36 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications