The aim of this study is to investigate how safe, effective, and well-tolerated multiple infusions of the experimental study treatment, emapalumab (the study medication) are in controlling this disease, as well as to check the concentrations of…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetics and Pharmacodynamics
* PK profile of emapalumab.
* Levels of circulating free IFNγ- at predose, and total IFNγ (free IFNγ+bound
to emapalumab) after initiation of emapalumab.
* Levels of the main IFNγ-induced chemokines (CXCL9, CXCL10).
* Correlation between chemokine levels (CXCL9, CXCL10) and levels of free
emapalumab, free IFNγ (pre-dose) and total IFNγ (exploratory analysis).
* Correlation of chemokine and total IFNγ levels, and laboratory parameters of
MAS severity, e.g. ferritin, platelet count, LFTs (exploratory analysis).
* Levels of other potential disease markers (e.g. sCD25, sCD163, IL-10, IL-6,
IL-18, TNFα).
* Levels (if any) of circulating antibodies against emapalumab to determine
immunogenicity (ADA).
In particular, based on:
* levels of circulating emapalumab
* levels of total IFNγ
* levels of main IFNγ-induced chemokines (namely CXCL9 and CXCL10)
a PK/PD modelling will be used to confirm that the proposed dose regimen is
adequate in relation to the IFNγ production in this patient population.
Safety
The tolerability and safety of emapalumab treatment will be assessed as follows:
* Incidence, severity, causality and outcomes of AEs (serious and non-serious),
with particular attention being paid to infections.
* Evolution of laboratory parameters, in particular CBC, LFTs, inflammatory
markers (ferritin and CRP) and coagulation parameters.
* Number of patients withdrawn from the study due to safety reasons.
Efficacy
An assessment of emapalumab efficacy in this patient population will be based
on the following variables:
* Number of patients achieving MAS remission by Week 8 after initiation of
emapalumab treatment.
* Time to MAS remission.
* Number of patients for whom at any time during the study glucocorticoids can
be tapered i) to the same (or lower) dose being administered before the
occurrence of MAS (in those patients who are already treated for the underlying
condition) or ii) by 50% (or less) of the dose administered at emapalumab
treatment start (in those patients who present with MAS at disease onset).
* Time to glucocorticoids tapering (as above described).
* Survival time.
* Number of patients withdrawn from the study due to lack of efficacy.
Secondary outcome
* All study variables are considered to be exploratory in this study, and no
hierarchy of endpoints has been specified, as the objective of this pilot study
is to collect and analyze data to confirm that the proposed dose regimen is
adequate in this patient population. Statistical methods will therefore focus
on summarizing the data collected using descriptive statistics and on
appropriate graphical presentations.
* For binary endpoints (MAS remission by Week 8, number of patients who taper
glucocorticoids, number of patients who discontinue due to lack of efficacy),
95% confidence intervals will be calculated for proportions.
* For time to event endpoints (time to MAS remission, time to achievement of
glucocorticoids tapering and time to death), Kaplan-Meier curves will be
calculated and summary statistics, such as medians, proportions event-free at
various time points will be calculated and presented, and 95% confidence
intervals calculated where possible.
* Data relating to safety will be listed and summarised using descriptive
statistics.
Background summary
The condition, MAS, is an illness in which there is a disproportionate
multiplication and activation of some cells responsible for controlling the
mechanisms of defense of the body (the immune system). Although they are found
in large numbers, these specific cells are unable to eliminate microbes and
viruses, but produce large quantities of molecules which cause exaggerated
inflammation within the body. This can cause extensive harm to the tissues and
organs and is a threat of life. To fight against this exaggerated inflammation
an urgent and aggressive treatment and constant medical supervision is required.
The experimental study treatment, emapalumab, has been created by a
biotechnology company, Sobi AG. The study treatment is a protein similar to
other proteins the body produces to fight against foreign substances or
infections.
Emapalumab has been selected because it inactivates a protein called interferon
gamma (IFNγ) which is believed to be responsible for the inflammation and
tissue damage in MAS patients. Therefore, by neutralizing IFNγ, the
inflammation present in the body may be halted, stopping organ damage and
restoring a healthier condition.
Emapalumab has already been given to 14 healthy adults and more than 30
children, up to a dose of 10 mg/kg in some patients.
Study objective
The aim of this study is to investigate how safe, effective, and well-tolerated
multiple infusions of the experimental study treatment, emapalumab (the study
medication) are in controlling this disease, as well as to check the
concentrations of emapalumab in blood and the speed at which it leaves the
body.The study treatment will be administered in combination with a steroid
(e.g., methylprednisolone). This study has an optional genetic research part.
The main objectives of the study are:
* To describe the pharmacokinetics (PK) profile of emapalumab.
* To confirm the proposed dosing regimen of emapalumab.
* To evaluate the safety and tolerability profile of intravenous (i.v.)
administrations of emapalumab.
* To preliminary assess the efficacy of emapalumab.
* To assess the levels of relevant markers, such as IFN* and main IFN*-induced
chemokines (CXCL9, CXCL10).
* To assess other potential disease markers (e.g. sCD25, sCD163, IL-10, IL-6,
IL-18, TNFα).
* To assess the immunogenicity of emapalumab.
Study design
Interventional Phase 2 study
Open-label, single arm, international, multicenter study.
Intervention
/
Study burden and risks
As long as the study treatment is present in blood, there are potential risks
linked to it:
• an infection may be picked up more easily than in a normal health status or
an infection in the past may come back, due to the action of the study
treatment on the immune system. This risk is already present as a result of
this condition and of some other medications/treatments that were previously
received or will be received for this condition, which also reduce the body*s
ability to fight infections. To minimise this risk, receiving preventative
medications will be continued as long as the study treatment is measurable in
the body. The study doctor will pay particular attention to monitor for any
signs of infection during the course of the study.
• The study treatment may have an interfering effect on vaccinations. It is
important to discuss with the study doctor if there is a need to have any
vaccinations as long as the activity of the study treatment emapalumab can be
detected in the blood.
• Since the study treatment is a protein that has not been produced by the
body, its introduction into blood might provoke production of antibodies
against it. To detect the occurrence of these antibodies against the study
treatment, blood analysis will be performed from time-to-time during the
study.
During, or shortly after, the infusion:
• The study treatment could cause an allergic reaction (e.g., rash), as could
any other protein-based medication. However, these reactions usually occur
after the first infusions. Since during and after the infusion there will be
close medical supervision, and immediate medical care will be received.
• The study treatment will be given through a central line (a long thin tube
which the study doctor will have placed in a vein in the chest through an
insertion point in the neck), to avoid multiple needle insertions whenever
possible. This is usually done under local anaesthetic to numb the area. The
study treatment administration will take approximately 1-2 hours and will be
closely monitored by a study doctor.
• Local inflammation at the infusion site, if a central line is not used:
symptoms could include warmth, redness, itching, bruising, swelling and pain at
the cannula site. This risk should be avoided by careful infusion monitoring,
which is planned in the study.
As the study treatment is an investigational medication, there might be side
effects that are not been yet identified.
You will find further information on risks related to study procedures in
Appendix E (see Informed Consent Form)
Ch. des Aulx 12
Plan-les-Ouates 1228
CH
Ch. des Aulx 12
Plan-les-Ouates 1228
CH
Listed location countries
Age
Inclusion criteria
1. Patients of both genders 2. For sJIA patients: confirmed sJIA diagnosis. For
patients presenting with MAS in the context of the onset of sJIA high
presumption of sJIA (as per Appendix A) will suffice for eligibility.AOSD
patients: confirmed AOSD diagnosis as per Yamaguchi criteria (Appendix E) 3.
Diagnosis of active MAS confirmed by the treating rheumatologist, having
ascertained the followings:
Febrile patient presenting with:
- Ferritin > 684 ng/mL
and any two of:
- Platelet count <= 181 x10^9/L
- AST levels > 48 U/L
- Triglycerides > 156 mg/dL
- Fibrinogen levels <= 360 mg/dL.
(see Appendix B), 4 Patient presenting 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 methylprednisolone
(mPDN) on 3 consecutive days).
High i.v. glucocorticoid dose 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. 5.Tocilizumab, TNF inhibitors and canakinumab, if
administered, have to be discontinued before emapalumab initiation. 6. 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. 7. 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 (failure rate of less than 1% per year) from screening
until 6 months after receiving last dose of the study drug.
Highly effective contraceptive measures include:
o Sexual abstinence
o Hormonal contraceptives: combination or progesterone only
o Intrauterine methods: intrauterine devices or systems
o Bilateral tubal occlusion
o Vasectomised partner
Males with partners(s) of child-bearing potential must agree to take
appropriate precautions (such as sexual abstinence, barrier contraception,
vasectomy) to avoid fathering a child from screening until 6 months after
receiving last dose of the study drug.
Exclusion criteria
1. Diagnosis of suspected or confirmed primary HLH or HLH consequent to a
neoplastic disease. 2.Active mycobacteria (typical and atypical), Histoplasma
Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections., 3.
Clinical suspicion of latent tuberculosis., 4. Positive serology for HIV
antibodies., 5. Presence of malignancy., 6. 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., 7. History of hypersensitivity or allergy to any
component of the study drug., 8. Receipt of a BCG vaccine within 12 weeks prior
to screening., 9. Receipt of live or attenuated live vaccines (other than BCG)
within 6 weeks prior to screening., 10. Pregnant or lactating female patients.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004223-23-NL |
| ClinicalTrials.gov | NCT03311854 |
| CCMO | NL61939.041.17 |