This study is currently recruiting participants.
Number
20-I-0132
Sponsoring Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 12 Years Max Age: 130 Years
Referral Letter Required
Yes
Population Exclusion(s)
Pregnant Women
Keywords
Eosinophilia; Leukocyte Disorders; Hematologic Diseases; Anti-Asthmatic Agents; Respiratory System Agents
Recruitment Keyword(s)
None
Condition(s)
Hypereosinophilic Syndrome (HES)
Investigational Drug(s)
Benralizumab
Investigational Device(s)
Intervention(s)
Other: Placebo Drug: Benralizumab
Supporting Site
National Institute of Allergy and Infectious Diseases
HES is a disease characterized by high levels of eosinophils (a type of white blood cell) in a person's blood and a build-up of eosinophils in some organs and tissues, which causes their dysfunction. Researchers want to see if a new drug can reduce the number of eosinophils in the body and help people with HES.
Objective:
To find out if benralizumab will work and be safe for the treatment of HES.
Eligibility:
People age 12 and older who have HES that is not well controlled.
Design:
Participants will be screened with:
-Physical exam with vital signs
-Blood and urine tests
-Electrocardiogram to check heart rhythm
-Ultrasound of the heart
-Spirometry (they will blow into a tube to measure lung capacity)
-Medicine and medical history.
During screening, participants will also take surveys about fatigue, symptoms, quality of life, and other topics. Demographic data will be collected. They will take corticosteroids by mouth for 2 days. Adult participants may have a tissue biopsy.
Some screening tests will be repeated during the study.
Participants will be put into 2 groups.
During the first part of the study, one group will get injections of the study drug once a month for 6 months. The other group will get injections of a placebo.
During the second part of the study, both groups will get injections of the study drug once a month for at least 1 year.
Participants will have monthly study visits. They will have extra visits if their symptoms get worse or flare.
Adult participants may take part in optional sub-studies.
Participation will last at least 18 months.
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INCLUSION CRITERIA: Informed Consent/Age/Gender 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. Type of Patients and Disease Characteristics 3. Documented diagnosis of HES (history of persistent eosinophilia >1500 cells/microliter without secondary cause on 2 examinations (interval >=1 month) 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. -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/microliter at Visit 1 (assessed by local laboratory). 8. Corticosteroid responsiveness defined as an AEC < 1000 cells/microliter 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. Reproduction 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: (a) Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal, (b) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable, (c) Intrauterine device, (d) Intrauterine hormone-releasing system, (e) Bilateral tubal occlusion, (f) 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), (g) 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). 10. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for >= 12 months prior to the planned date of enrolment without an alternative medical cause. The following age-specific requirements apply: (a) Women < 50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels are in the postmenopausal range. Until FSH is documented to be within menopausal range, the patient should be treated as a WOCBP. (b) Women >= 50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. Other 11. French patients: In France, a patient will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category. EXCLUSION CRITERIA: Medical Conditions 1. Life-threatening HES and/or HES complication(s) as judged by the investigator: (a) Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomisation. (b) 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. (c) 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. (a) 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. (b) ALT or AST level >= 3 x ULN during the screening period (AST or ALT > 5 x 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: (a) 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 (b) Patients with basal cell or superficial squamous skin cancer. (c) 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. 13. Any clinically significant abnormal findings in HES physical examination, vital signs, haematology, or clinical chemistry, during the screening period, 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. Prior/concomitant Therapy 14. Evidence of prior benralizumab treatment failure. 15. Treatment with injectable (SC, IV, or IM) corticosteroids in the 4-week period prior to randomisation. 16. Receipt of any IP within the past 30 days or 5 half-lives, whichever is longer, prior to Visit 1, or current participation in any other interventional clinical study (with the exception of "registry"/"cohort" trials that may include periodic biological sampling and/or patient questionnaires but in which no other unlicensed IP is administered). 17. Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer. Patients on stable therapy for at least 3 months before randomisation who intend to stay on treatment throughout the study with marketed biologics that are not likely to interfere with the assessment of safety and/or efficacy of benralizumab (eg, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, ocular, cardiovascular, or metabolic diseases) can participate in the study. 18. Receipt of live attenuated vaccines 30 days prior to Visit 1. Other Exclusions 19. History of hypersensitivity (including anaphylaxis) to any biologic therapy (including benralizumab) or any steroid or steroid-containing product. Known history of allergy or reaction to any component of the IP formulation. 20. Receipt of Ig or blood products within 30 days prior to Visit 1. 21. Patients with a known or suspected history of alcohol or substance abuse at Visit 1 which, in the opinion of the investigator, could interfere with the patient's proper completion of the protocol requirements. 22. For women only: Currently pregnant, breastfeeding, or lactating women (a) Both urine and serum pregnancy tests will be done for WOCBP at Visit 1. If serum test is positive, the patient should be excluded.
Informed Consent/Age/Gender
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.
Type of Patients and Disease Characteristics
3. Documented diagnosis of HES (history of persistent eosinophilia >1500 cells/microliter without secondary cause on 2 examinations (interval >=1 month) 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.
-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/microliter at Visit 1 (assessed by local laboratory).
8. Corticosteroid responsiveness defined as an AEC < 1000 cells/microliter 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.
Reproduction
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:
(a) Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal,
(b) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable,
(c) Intrauterine device,
(d) Intrauterine hormone-releasing system,
(e) Bilateral tubal occlusion,
(f) 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),
(g) 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).
10. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for >= 12 months prior to the planned date of enrolment without an alternative medical cause. The following age-specific requirements apply:
(a) Women < 50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and FSH levels are in the postmenopausal range. Until FSH is documented to be within menopausal range, the patient should be treated as a WOCBP.
(b) Women >= 50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
Other
11. French patients: In France, a patient will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
EXCLUSION CRITERIA:
Medical Conditions
1. Life-threatening HES and/or HES complication(s) as judged by the investigator:
(a) Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomisation.
(b) 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.
(c) 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.
(a) 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.
(b) ALT or AST level >= 3 x ULN during the screening period (AST or ALT > 5 x 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:
(a) 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
(b) Patients with basal cell or superficial squamous skin cancer.
(c) 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.
13. Any clinically significant abnormal findings in HES physical examination, vital signs, haematology, or clinical chemistry, during the screening period, 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.
Prior/concomitant Therapy
14. Evidence of prior benralizumab treatment failure.
15. Treatment with injectable (SC, IV, or IM) corticosteroids in the 4-week period prior to randomisation.
16. Receipt of any IP within the past 30 days or 5 half-lives, whichever is longer, prior to Visit 1, or current participation in any other interventional clinical study (with the exception of "registry"/"cohort" trials that may include periodic biological sampling and/or patient questionnaires but in which no other unlicensed IP is administered).
17. Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer. Patients on stable therapy for at least 3 months before randomisation who intend to stay on treatment throughout the
study with marketed biologics that are not likely to interfere with the assessment of safety and/or efficacy of benralizumab (eg, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, ocular, cardiovascular, or metabolic diseases) can participate in the
study.
18. Receipt of live attenuated vaccines 30 days prior to Visit 1.
Other Exclusions
19. History of hypersensitivity (including anaphylaxis) to any biologic therapy (including benralizumab) or any steroid or steroid-containing product. Known history of allergy or reaction to any component of the IP formulation.
20. Receipt of Ig or blood products within 30 days prior to Visit 1.
21. Patients with a known or suspected history of alcohol or substance abuse at Visit 1 which, in the opinion of the investigator, could interfere with the patient's proper completion of the protocol requirements.
22. For women only: Currently pregnant, breastfeeding, or lactating women
(a) Both urine and serum pregnancy tests will be done for WOCBP at Visit 1. If serum test is positive, the patient should be excluded.
Principal Investigator
Referral Contact
For more information: