Study to Evaluate Safety and Efficacy of Benralizumab in Subjects With Hypereosinophilic Syndrome

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Brief Title

Study to Evaluate Safety and Efficacy of Benralizumab in Subjects With Hypereosinophilic Syndrome

Official Title

A Phase 2a Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subcutaneous Benralizumab (MEDI-563) in Reducing Eosinophilia in Subjects With Hypereosinophilic Syndrome (HES)

Brief Summary

      Background:

      - Eosinophils are white blood cells that help fight infections. High eosinophil levels can
      damage people s organs, causing hypereosinophilic syndrome (HES). Researchers want to study
      if the drug benralizumab can help people with HES.

      Objective:

      - To test if benralizumab can safely decrease eosinophils in people with HES.

      Eligibility:

      - Adults age 18-65 who have been on stable HES therapy for at least 1 month but still have
      symptoms and high eosinophil levels.

      Design:

        -  Participants will be screened with medical history, physical exam, and urine and blood
           tests. They will take simple heart and lung tests.

        -  Participants will also have a bone marrow biopsy. A numbing medicine is injected into
           the outer covering of the bone. Then a needle is inserted into the bone. A fast suction
           movement takes bone marrow cells.

        -  Phase 1: Participants will randomly receive either the study drug or placebo as an
           injection.

        -  They will have daily visits for the next 3 days, then 4 weekly visits, and then 4
           biweekly visits. Each time, they will have medical history, physical exam, blood tests,
           and a check of side effects.

        -  They will receive another dose of the study drug or placebo at 1 month and 2 months
           after the first injection.

        -  Phase 2 repeats the Phase 1 schedule. All participants will receive the study drug.

        -  At 1 visit, participants will also receive a vaccine. At 4 visits, they will repeat the
           heart and lung tests. They will also have one other bone marrow biopsy.

        -  After week 24, participants will receive the study drug either 6 times over 6 months or
           twice over 6 months.
    

Detailed Description

      Hypereosinophilic syndrome (HES) is a rare group of heterogeneous disorders characterized by
      marked peripheral eosinophilia (>1500/(micro)L) and evidence of eosinophil-associated tissue
      damage. Although a high proportion of patients respond initially to corticosteroid therapy,
      high doses are often necessary to control the eosinophilia and clinical symptoms, and many
      patients become relatively refractory to therapy and/or develop serious side effects. IL-5
      receptor (alpha) (IL-5R (alpha) expression in humans is restricted to eosinophils, basophils,
      mast cells and their precursors and is, therefore, an ideal target for the therapy of HES. To
      date, there have been no safety concerns with benralizumab (anti-IL-5R(alpha)) in phase 1, 2
      and 3 trials in asthma and efficacy data is promising. In order to explore the safety and
      efficacy of benralizumab in the treatment of HES, 20 adults (men and non-pregnant women,
      18-75 years of age) with HES who are symptomatic with AEC >1000/(micro)L on stable HES
      therapy for at least 1 month will be recruited for this randomized, placebo-controlled,
      double-blind phase 2 trial. Benralizumab (30 mg) or placebo will be administered sc at weeks
      0, 4, and 8. Eosinophil counts will be blinded for a subject and background HES therapy will
      not be tapered until that subject has been on study for 13 weeks. At weeks 12, 16, and 20,
      all subjects will receive a sc injection of benralizumab. Subjects demonstrating a response
      at the 24 week visit (eosinophil count <1000/(alpha) L and stable or improved clinical
      symptoms without an increase in background HES therapy) will continue to receive additional
      30 mg sc injections every 4 weeks. Following the initial dose of benralizumab or placebo and
      the first open-label dose of benralizumab, subjects will be followed daily for 3 days, weekly
      for 4 weeks, and every 2 weeks for 8 weeks. Subsequent visits will be at 4 weeks intervals
      for responders and 12 weeks intervals for non-responders for a minimum of two years. Subjects
      with stable and complete response for greater than or equal to 2 years may be eligible to
      receive benralizumab at a dosing interval of every 8 weeks. Subjects will receive
      diphtheria-tetanus-acellular pertussis (TdaP) booster immunization at the 22 week visit.
      Titers will be measured 6 weeks after immunization.The primary endpoint of the study is a 50%
      reduction in peripheral blood eosinophilia on stable background therapy at 12 weeks
      post-initiation of study drug. Secondary endpoints will include absolute eosinophil count,
      the frequency and severity of adverse events, reduction in signs and symptoms of HES, tissue
      eosinophilia, numbers of eosinophils, mast cells and their precursors in bone marrow, levels
      of markers of eosinophil and mast cell activation, eosinophil count and background HES
      therapy at 1 year, pharmacokinetics and anti-drug antibody (ADA) levels and eosinophil count
      after 24 weeks of every 8 week dosing. Exploratory endpoints will address predictors of
      response to benralizumab and the impact of eosinophil depletion on vaccine responses and
      glucose homeostasis. Subjects who complete the study and for whom benralizumab provides
      sustained clinical benefit, may be eligible to receive drug on an open-label extension
      protocol until regulatory approval and commercial availability of the marketed drug to
      prescribing physicians (for any indication), or until development of benralizumab is
      discontinued by MedImmune.
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

To determine the efficacy of 3 doses of sc benralizumab in reducing eosinophilia in subjects with PDGFRA- negative HES

Secondary Outcome

 To assess the safety of sc benralizumab in reducing eosinophilia in subjects with HES To assess the effect of benralizumab on end organ manifestations of HES

Condition

Respiratory System Agents

Intervention

benralizumab

Study Arms / Comparison Groups

 Drug
Description:  Benralizumab (30mg) will be administered sc every 4 weeks for 3 doses (at weeks 0, 4 and 8). Eosinophil counts will be blinded during this time and background HES therapy will not be tapered.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

22

Start Date

May 19, 2014

Completion Date

December 31, 2022

Primary Completion Date

December 31, 2022

Eligibility Criteria

        -  INCLUSION CRITERIA:

        A subject will be eligible for participation in the study only if all of the following
        criteria apply:

          1. Male or female subject greater than or equal to18 and less than or equal to 75 years
             of age at screening.

          2. A female subject is eligible for this study only if she is not pregnant or
             breast-feeding and one of the following:

               1. Of childbearing potential but agrees to practice effective contraception, as
                  determined by the PI, or abstinence throughout the study and for 3 months after
                  administration of the last dose of investigational study drug

               2. Of non-child-bearing potential

        Females of non-child-bearing potential are defined as females with functioning ovaries with
        a documented history of tubal ligation or hysterectomy or females who are post-menopausal,
        as defined by 12 months of spontaneous amenorrhea with an appropriate clinical profile,
        e.g. age appropriate, >45 years, in the absence of hormone replacement therapy. In
        questionable cases, a blood sample for follicle stimulating hormone and estradiol will be
        obtained to confirm child-bearing potential.

        Acceptable methods of contraception may include one or more of the following:

        1) male partner who is sterile prior to the female subject s entry into the study and is
        the sole sexual partner for the female subject; 2) implants of levonorgestrel; 3)
        injectable progestogen, 4) an intrauterine device with a documented failure rate of <1%;
        and 5) double barrier methods including diaphragm or condom with a spermicide.

        3) A male subject is eligible for this study only if he is one of the following:

          1. Surgically sterile

          2. Agrees to practice effective contraception (see above) or abstinence throughout the
             study and for 3 months after the last administration of the investigational study drug

             4) Documented diagnosis of HES (history of persistent eosinophilia >1500/(micro) L
             without secondary cause and evidence of end organ manifestations attributable to the
             eosinophilia)

             5) Signs or symptoms of HES and AEC >1000/(micro) L on stable HES therapy for greater
             than or equal to 1 month at the time of enrollment

             6) Participation in protocol 94-I-0079 (Activation and function of eosinophils in
             conditions with blood or tissue eosinophilia)

             7) Agrees to storage of samples for study

             Participation of Women:

             Contraception: The effects of benralizumab on the developing human fetus are unknown.
             For this reason, men and women of childbearing potential must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry and for the duration of study participation. Females of childbearing-age must
             have a negative pregnancy test result prior to receiving benralizumab. During the
             course of the study, if a woman becomes pregnant or suspects she is pregnant, she
             should inform the study staff and her primary care physician immediately. If a subject
             becomes pregnant, the investigational drug will be discontinued immediately, and the
             subject will be counselled as to how to resume approved therapeutic options in
             consultation with an obstetric provider.

             EXCLUSION CRITERIA:

             A subject will be excluded from participation in the study if any of the following
             criteria apply at the time of enrollment:

               1. Subjects with life-threatening or other serious illness or clinical manifestation
                  of HES deemed inappropriate for inclusion in study per the principal
                  investigator, including but not restricted to severe cardiac involvement and
                  prior thromboembolic disease.

               2. Human immunodeficiency virus (HIV) or other known immunodeficiency

               3. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or
                  a positive medical history for hepatitis B or C. Patients with a history of
                  hepatitis B vaccination without history of hepatitis B are allowed to enroll

               4. Presence of FIP1L1/PDGFRA or another known imatinib-sensitive mutation

               5. Diagnosis of systemic mastocytosis or serum tryptase level >40 ng/mL

               6. Known lymphoma, hematological malignancy, advanced and metastatic solid tumors
                  and/or subjects who are under chemotherapy, radiotherapy or interleukin 2
                  treatment

               7. Known history of allergic or anaphylactic reaction to previous antibody therapy,
                  including intravenous immunoglobulin and licensed or experimental monoclonal
                  antibodies.

               8. A helminth parasitic infection diagnosed within 24 weeks prior to the date
                  informed consent is obtained

               9. Acute bacterial or viral infection (subjects may be enrolled once the acute
                  infection has resolved).

              10. Receipt of intravenous immunoglobulin (IVIG) within 30 days prior to the date
                  informed consent is obtained

              11. Receipt of any marketed (eg omalizumab) or investigational biologic within 4
                  months or 5 half-lives prior to the date informed consent is obtained, whichever
                  is longer

              12. Receipt of live attenuated vaccines 30 days prior to the date of randomization

              13. Receipt of inactive/killed vaccinations (e.g. inactive influenza) are allowed
                  provided they are not administered within 1 week before/after any study visit

              14. Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior
                  to the date informed consent is obtained, whichever is longer

              15. History of alcohol or drug abuse within 12 months prior to the date informed
                  consent is obtained

              16. Previous treatment with benralizumab (MEDI-563).

             Co-enrollment Guidelines: Co-enrollment in other trials is restricted, other than
             enrollment on observational studies or those evaluating the use of a licensed
             medication. Study staff should be notified of co-enrollment as it may require the
             approval of the Investigator.

             Justification for Exclusion of Children:

             Because there are insufficient data regarding dosing or adverse events available in
             adults with HES to judge the potential risk in children, children are excluded from
             this study.
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Amy D Klion, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02130882

Organization ID

140081

Secondary IDs

14-I-0081

Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

 AstraZeneca

Study Sponsor

Amy D Klion, M.D., Principal Investigator, National Institute of Allergy and Infectious Diseases (NIAID)


Verification Date

December 3, 2019