Informations générales (source: ClinicalTrials.gov)
A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 24-Week Phase III Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES) (NATRON)
Interventional
Phase 3
AstraZeneca (Voir sur ClinicalTrials)
juillet 2020
avril 2027
04 mai 2025
This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled,
24-week Phase III study to compare the efficacy and safety of benralizumab versus placebo
administered by SC injection Q4W in patients with hypereosinophilic syndrome (HES). This
study comprises 2 distinct periods (together defined as the 'main study'): A 24-week, DB
treatment period, during which patients will be randomised to receive either benralizumab
or placebo, in addition to their prior stable HES background therapy, and an open-label
extension (OLE) period, during which all patients will receive benralizumab.
The primary database lock (DBL) will occur when approximately 38 patients have had their
first HES worsening/flare event during the DB treatment period and all randomised
patients have had the opportunity to be followed up for the 24-week DB treatment period.
A patient must complete the 24-week DB treatment period on investigational product (IP)
to be eligible to enter the OLE treatment period. The final DBL will occur after the last
patient completes the OLE.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| HOPITAL FOCH | JEAN-EMMANUEL KAHN | 05/05/2025 07:12:05 | Contacter | ||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Research Site - 31059 - Toulouse - France | Contact (sur clinicalTrials) | ||||
| Research Site - 33604 - Pessac - France | Contact (sur clinicalTrials) | ||||
| Research Site - 59037 - Lille - France | Contact (sur clinicalTrials) | ||||
| Research Site - 67091 - Strasbourg - France | Contact (sur clinicalTrials) | ||||
| Research Site - 75571 - PARIS Cedex 12 - France | Contact (sur clinicalTrials) | ||||
| Research Site - 92151 - Suresnes Cedex - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
Inclusion Criteria
1. Provision of the signed and dated written informed consent of the patient or the
patient's legally authorised representative, and informed assent from the patient
(per local regulations) prior to any mandatory study-specific procedures, sampling,
and analyses
2. Males and females 12 years of age and older at the time of signing the ICF
3. Documented diagnosis of HES (history of persistent eosinophilia > 1500 cells/μL
without secondary cause on 2 examinations [interval ≥ 1 month; Valent et al 2012]
and evidence of end organ manifestations attributable to the eosinophilia)
4. Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene
translocation
5. Stable HES treatment dose(s) and regimen for ≥ 4 weeks at the time of Visit 1
6. Signs or symptoms of HES worsening/flare and/or laboratory abnormalities indicative
of HES worsening/flare (other than isolated eosinophilia) at Visit 1 OR a documented
history of 2 or more HES worsening/flares within 12 months prior to Visit 1
requiring an escalation in therapy
a. At least one flare within the past 12 months must not be related to a decrease in
HES therapy during the 4 weeks prior to the flare
7. AEC ≥ 1000 cells/μL at Visit 1 (assessed by local laboratory)
8. Corticosteroid responsiveness defined as an AEC < 1000 cells/μL after a 2-day course
of OCS (prednisone/prednisolone) 1 mg/kg/day at Visit 2 (assessed by local
laboratory). Other OCSs in equivalent doses are permitted
9. WOCBP must agree to use a highly effective method of birth control (confirmed by the
investigator) from enrolment, throughout the study duration, and within 12 weeks
after last dose of IP and have a negative urine dipstick pregnancy test result on
Visit 1. Highly effective methods of birth control (those that can achieve a failure
rate of less than 1% per year when used consistently and correctly) include:
1. Combined (oestrogen- and progestogen-containing) hormonal contraception
associated with inhibition of ovulation: oral, intravaginal, or transdermal
2. Progestogen-only hormonal contraception associated with inhibition of
ovulation: oral, injectable, or implantable
3. Intrauterine device
4. Intrauterine hormone-releasing system
5. Bilateral tubal occlusion
6. Sexual abstinence, ie, refraining from heterosexual intercourse (the
reliability of sexual abstinence needs to be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the
patient)
7. Vasectomised sexual partner (provided that partner is the sole sexual partner
of the WOCBP study patient and that the vasectomised partner has received
medical assessment of the surgical success)
Exclusion Criteria
1. Life-threatening HES and/or HES complication(s) as judged by the investigator:
1. Medical intervention for HES-related life-threatening event(s) within 12 weeks
prior to randomization
2. History of thrombotic complications, stroke, or significant cardiac damage
related to HES, if the respective events were life threatening and currently
represent a risk of life-threatening disease complications. Events that
occurred in the past but considered resolved or stable, can be accepted if, as
per investigator's judgment, participation in the study will not put the
patient at risk
3. Disease severity that in the opinion of the investigator makes the patient
inappropriate for inclusion in the study
2. Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known
imatinib-sensitive mutation
3. Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
4. Known, preexisting, clinically significant endocrine, autoimmune, metabolic,
neurological, renal, gastrointestinal, hepatic, haematological, respiratory, or any
other system abnormalities that are not associated with HES and are uncontrolled
with standard treatment which, in the opinion of the investigator, may put the
patient at risk because of his/her participation in the study, or may influence the
results of the study, or the patient's ability to complete the entire duration of
the study
5. Hypereosinophilia of unknown significance
6. Cardiovascular: Documented history of any clinically significant cardiac damage,
clinically significant echocardiography (if available) or ECG findings within 12
months prior to Visit 1 or clinically significant ECG findings at screening that in
the opinion of the investigator may put the patients at risk
7. Known currently active liver disease
1. Chronic stable hepatitis B and C (including positive testing for hepatitis B
surface antigen or hepatitis C antibody) or other stable chronic liver disease
are acceptable if patient otherwise meets eligibility criteria. Stable chronic
liver disease should generally be defined by the absence of ascites,
encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices,
or persistent jaundice, or cirrhosis
2. ALT or AST level ≥ 3 × ULN during the screening period (AST or ALT > 5 × ULN if
documented HES with liver manifestations). Transient increase of AST/ALT level
that resolves by the time of randomisation is acceptable if, in the
investigator's opinion, the patient does not have an active liver disease and
meets other eligibility criteria
8. Current or history of malignancy within 5 years before the screening visit with the
following exceptions:
1. Patients treated for in situ carcinoma of the cervix who have completed
curative therapy and are in remission for at least 12 months prior to signing
the informed consent and
2. Patients with basal cell or superficial squamous skin cancer
3. Patients who have had other malignancies are eligible provided that the patient
is in remission and curative therapy was completed at least 5 years prior to
the date informed consent was obtained
9. Diagnosis of systemic mastocytosis
10. Chronic or ongoing active infections requiring systemic treatment, as well as
clinically significant viral, bacterial, or fungal infection within 4 weeks prior to
Visit 1
11. A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has
not been treated or has failed to respond to standard of care therapy. A
confirmation of a complete resolution of any helminth parasitic infection prior to
Visit 1 should be available
12. A history of known immunodeficiency disorder other than that explained by the use of
OCS or other therapy taken for HES. Positive HIV test
14. Evidence of prior benralizumab treatment failure
1. Provision of the signed and dated written informed consent of the patient or the
patient's legally authorised representative, and informed assent from the patient
(per local regulations) prior to any mandatory study-specific procedures, sampling,
and analyses
2. Males and females 12 years of age and older at the time of signing the ICF
3. Documented diagnosis of HES (history of persistent eosinophilia > 1500 cells/μL
without secondary cause on 2 examinations [interval ≥ 1 month; Valent et al 2012]
and evidence of end organ manifestations attributable to the eosinophilia)
4. Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene
translocation
5. Stable HES treatment dose(s) and regimen for ≥ 4 weeks at the time of Visit 1
6. Signs or symptoms of HES worsening/flare and/or laboratory abnormalities indicative
of HES worsening/flare (other than isolated eosinophilia) at Visit 1 OR a documented
history of 2 or more HES worsening/flares within 12 months prior to Visit 1
requiring an escalation in therapy
a. At least one flare within the past 12 months must not be related to a decrease in
HES therapy during the 4 weeks prior to the flare
7. AEC ≥ 1000 cells/μL at Visit 1 (assessed by local laboratory)
8. Corticosteroid responsiveness defined as an AEC < 1000 cells/μL after a 2-day course
of OCS (prednisone/prednisolone) 1 mg/kg/day at Visit 2 (assessed by local
laboratory). Other OCSs in equivalent doses are permitted
9. WOCBP must agree to use a highly effective method of birth control (confirmed by the
investigator) from enrolment, throughout the study duration, and within 12 weeks
after last dose of IP and have a negative urine dipstick pregnancy test result on
Visit 1. Highly effective methods of birth control (those that can achieve a failure
rate of less than 1% per year when used consistently and correctly) include:
1. Combined (oestrogen- and progestogen-containing) hormonal contraception
associated with inhibition of ovulation: oral, intravaginal, or transdermal
2. Progestogen-only hormonal contraception associated with inhibition of
ovulation: oral, injectable, or implantable
3. Intrauterine device
4. Intrauterine hormone-releasing system
5. Bilateral tubal occlusion
6. Sexual abstinence, ie, refraining from heterosexual intercourse (the
reliability of sexual abstinence needs to be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the
patient)
7. Vasectomised sexual partner (provided that partner is the sole sexual partner
of the WOCBP study patient and that the vasectomised partner has received
medical assessment of the surgical success)
Exclusion Criteria
1. Life-threatening HES and/or HES complication(s) as judged by the investigator:
1. Medical intervention for HES-related life-threatening event(s) within 12 weeks
prior to randomization
2. History of thrombotic complications, stroke, or significant cardiac damage
related to HES, if the respective events were life threatening and currently
represent a risk of life-threatening disease complications. Events that
occurred in the past but considered resolved or stable, can be accepted if, as
per investigator's judgment, participation in the study will not put the
patient at risk
3. Disease severity that in the opinion of the investigator makes the patient
inappropriate for inclusion in the study
2. Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known
imatinib-sensitive mutation
3. Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
4. Known, preexisting, clinically significant endocrine, autoimmune, metabolic,
neurological, renal, gastrointestinal, hepatic, haematological, respiratory, or any
other system abnormalities that are not associated with HES and are uncontrolled
with standard treatment which, in the opinion of the investigator, may put the
patient at risk because of his/her participation in the study, or may influence the
results of the study, or the patient's ability to complete the entire duration of
the study
5. Hypereosinophilia of unknown significance
6. Cardiovascular: Documented history of any clinically significant cardiac damage,
clinically significant echocardiography (if available) or ECG findings within 12
months prior to Visit 1 or clinically significant ECG findings at screening that in
the opinion of the investigator may put the patients at risk
7. Known currently active liver disease
1. Chronic stable hepatitis B and C (including positive testing for hepatitis B
surface antigen or hepatitis C antibody) or other stable chronic liver disease
are acceptable if patient otherwise meets eligibility criteria. Stable chronic
liver disease should generally be defined by the absence of ascites,
encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices,
or persistent jaundice, or cirrhosis
2. ALT or AST level ≥ 3 × ULN during the screening period (AST or ALT > 5 × ULN if
documented HES with liver manifestations). Transient increase of AST/ALT level
that resolves by the time of randomisation is acceptable if, in the
investigator's opinion, the patient does not have an active liver disease and
meets other eligibility criteria
8. Current or history of malignancy within 5 years before the screening visit with the
following exceptions:
1. Patients treated for in situ carcinoma of the cervix who have completed
curative therapy and are in remission for at least 12 months prior to signing
the informed consent and
2. Patients with basal cell or superficial squamous skin cancer
3. Patients who have had other malignancies are eligible provided that the patient
is in remission and curative therapy was completed at least 5 years prior to
the date informed consent was obtained
9. Diagnosis of systemic mastocytosis
10. Chronic or ongoing active infections requiring systemic treatment, as well as
clinically significant viral, bacterial, or fungal infection within 4 weeks prior to
Visit 1
11. A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has
not been treated or has failed to respond to standard of care therapy. A
confirmation of a complete resolution of any helminth parasitic infection prior to
Visit 1 should be available
12. A history of known immunodeficiency disorder other than that explained by the use of
OCS or other therapy taken for HES. Positive HIV test
14. Evidence of prior benralizumab treatment failure