Study to Evaluate Safety and Efficacy of Dexpramipexole (KNS-760704) in Subjects With Hypereosinophilic Syndrome

Related Clinical Trial
MAP to Provide Access to Nilotinib, for Patients With HES Eosinophilia Diagnosis A Multi-center, Open-label Extension, Safety Study of Mepolizumab in Subjects With Hypereosinophilic Syndrome (HES) From Study 200622 This Record Contains Information About the Mepolizumab Compassionate Use (CU) Product Activities: 104317: CU and Long-Term Access Study of Mepolizumab in HES. 201956:A Long-term Access Programme for Subjects With Severe Asthma 112562: Expanded Access for Patients With Hypereosinophilic Efficacy of Imatinib Mesylate in Hypereosinophilic Syndromes Study to Evaluate Safety and Efficacy of Benralizumab in Subjects With Hypereosinophilic Syndrome Anti-Interleukin-5 (IL-5) Study for Hypereosinophilic Syndrome A Longitudinal Study of Familial Hypereosinophilia (FE): Natural History and Markers of Disease Progression Phase II Gleevec Idiopathic Hypereosinophilic Syndrome Anti-Interleukin-5 Antibody to Treat Hypereosinophilic Syndrome Intravenous Mepolizumab In Subjects With Hypereosinophilic Syndromes (HES) Study to Evaluate Safety and Efficacy of Dexpramipexole (KNS-760704) in Subjects With Hypereosinophilic Syndrome Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome Steroid Treatment for Hypereosinophilic Syndrome Natural History of Hypereosinophilia and Hypereosinophilic Syndromes A Study to Determine the Safety and Efficacy of Imatinib Mesylate in Patients With Idiopathic Hypereosinophilic Syndrome Identification of New Markers in the Hypereosinophilic Syndrome A Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES) Open-Label Extension Of Intravenous Mepolizumab In Patients With Hypereosinophilic Syndrome

Brief Title

Study to Evaluate Safety and Efficacy of Dexpramipexole (KNS-760704) in Subjects With Hypereosinophilic Syndrome

Official Title

An Open-Label, Proof-of-Concept Study to Evaluate the Safety and Efficacy of Dexpramipexole (KNS-760704) in Subjects With Hypereosinophilic Syndrome

Brief Summary

      Background:

      - Eosinophils are white blood cells that fight infections. In people with hypereosinophilic
      syndrome (HES), eosinophil levels are too high and can damage their organs. HES is usually
      treated with steroids, but steroids can cause side effects and stop working over time.
      Researchers want to see if a drug called dexpramipexole, being developed by Knopp
      Pharmaceuticals, can help people with HES to reduce their steroid dose.

      Objective:

      - To test whether dexpramipexole can reduce the steroid dose needed to control eosinophilia
      and HES symptoms.

      Eligibility:

      - Adults 18 and older with HES who respond to steroids, but need more than 10 mg daily to
      control eosinophilia and symptoms.

      Design:

        -  The study will last 9 months with 6 visits to NIH.

        -  Participants will be screened with medical history, physical exam, and urine and blood
           samples.

        -  Participants steroids will be tapered to the lowest effective dose. During this time,
           blood will be drawn weekly. Participants will take this dose for 2 weeks before starting
           the study drug.

        -  Participants will take the study drug twice daily by mouth for 12 weeks along with
           steroids. The steroid dose will not be decreased during this time and participants will
           be seen monthly for a medical history, physical examination and blood work.

        -  Just before and 12 weeks after starting the study drug, the following tests will be
           performed:

        -  medical history and physical exam

        -  blood and urine tests

        -  lung function tests

        -  electrocardiogram (measures heart electrical activity)

        -  echocardiogram (takes pictures of the heart using sound waves)

        -  bone marrow biopsy (a needle inserted into the hip bone that removes bone marrow cells
           for study)

        -  After 12 weeks, the participants steroid dose will be tapered again to the lowest
           effective dose while on study drug.

        -  Two weeks after the lowest effective dose is reached, participants will return for a
           medical history, physical examination, blood work, lung and heart tests.

        -  Participants who respond to the study drug may be able to continue to receive the drug
           on a planned separate study.

        -  Four weeks after stopping the study drug, participants will have medical history,
           physical exam, and blood tests.
    

Detailed Description

      Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by
      peripheral eosinophilia and evidence of eosinophil-related end organ 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.

      Dexpramipexole (KNS 760704) is a synthetic aminobenzothiazole shown to safely reduce blood
      eosinophils counts in individuals with amyotrophic lateral sclerosis (ALS) in several
      clinical trials. The purpose of this proof-of- concept study is to evaluate the effect of
      dexpramipexole, an orally bioavailable small molecule, on circulating and tissue eosinophils
      in 10 subjects with HES. Following completion of eligibility assessments, subjects with
      absolute eosinophil count (AEC) < 1000/uL will enter a lead-in period, during which a
      standardized weekly corticosteroid taper will be undertaken to establish a "minimally
      effective corticosteroid dose" in each study subject. For subjects whose symptoms are stable
      but AEC > 1000/uL at the time of enrollment, the steroid dose at the time of enrollment will
      be defined as the minimally effective corticosteroid dose and no taper will be performed.
      Once the minimally effective corticosteroid dose is established, treatment with
      dexpramipexole 150 mg twice daily will begin. A standardized corticosteroid taper will begin
      after 12 weeks of treatment with dexpramipexole to determine the "minimally effective
      corticosteroid dose on dexpramipexole". Eosinophil counts and routine chemistries will be
      monitored weekly during corticosteroid tapering. End organ assessment, including
      echocardiogram, pulmonary function testing, and other studies as appropriate will be
      performed at study baseline, initiation of dexpramipexole therapy, 3 months after initial
      dosing with dexpramipexole, and the end of study visit. Bone marrow assessment will be
      performed prior to and after 12 weeks of dexpramipexole. Drug levels will be assessed prior
      to dexpramipexole and at week 12 and week 24 of dosing.

      The primary efficacy endpoint will be the number of subjects with a greater than or equal to
      50 % change in prednisone (or equivalent) dose to maintain absolute eosinophil count (AEC) at
      or below baseline (pre-enrollment) levels and control clinical symptoms (responder analysis).
      Assuming that 10 patients received study drug per protocol, at least 4 of them will need to
      meet this endpoint to significantly show (at the usual two-sided 5% level, equivalent to the
      onesided 2.5% level) that at least 10% of patients respond to dexpramipexole (exact binomial
      test). Safety will be assessed as the incidence of adverse events (AEs) (including serious
      adverse events [SAEs]), vital signs, clinical laboratory assessments, physical examination,
      electrocardiogram (ECG) tests, and body weight. Exploratory endpoints will include
      determination of the effect of dexpramipexole on measures of eosinophil activation,
      cytokine/chemokine profile and other immunologic parameters, and reduction of tissue
      eosinophils.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

The corticosteroid dose after treatment with 150 mg twice daily of dexpramipexole as a percentage of the corticosteroid dose prior to treatment

Secondary Outcome

 Reduction in circulating eosinophil and bone marrow eosinophil count after 3 months of treatment with dexpramipexole (prior to steroid taper)

Condition

Hypereosinophilic Syndrome

Intervention

Dexpramipexole

Study Arms / Comparison Groups

 Dexpramipexole
Description:  Dexpramipexole treatment

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

15

Start Date

March 14, 2014

Completion Date

October 23, 2019

Primary Completion Date

December 30, 2016

Eligibility Criteria

        -  INCLUSION CRITERIA:

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

          1. The subject is male or female, age greater than or equal to 18 years

          2. The subject has a documented history of HES requiring greater than or equal to 10 mg
             prednisone (or equivalent) to maintain disease control.

             HES is defined as 1) peripheral blood eosinophilia (>1500 eosinophils/microL) on at
             least two occasions, 2) signs and symptoms of organ system involvement attributable to
             the eosinophilia, and 3) exclusion of secondary causes of eosinophilia, such as
             parasitic helminth infection, drug hypersensitivity and neoplasms, for which
             appropriate therapy is directed at the underlying cause

          3. HES symptoms are stable on the current corticosteroid dose.

          4. The subject agrees to storage of samples for study.

          5. Females are eligible for this study if they are:

        (1) of non-childbearing potential (i.e., women who have had a hysterectomy or tubal
        ligation or are postmenopausal as defined by no menses in 1 year); OR

        (2) of childbearing potential but willing to practice effective contraception or abstinence
        during administration of the study drug and for 3 months after administration of the
        investigational study drug (dexpramipexole).

        Participation of Women:

        Contraception: Pre-clinical animal data demonstrated some fetal risk, suggesting there may
        a human reproductive risk. Subjects must agree not to become pregnant. Females of
        childbearing potential must have a pregnancy test before the first dose of dexpramipexole.
        Because of the risk involved, subjects and their partners must use two methods of birth
        control. They must continue to use both methods for 3 months after stopping the study drug.
        Two methods of birth control may be selected from the list included below:

          -  Hormonal contraception

          -  Male or female condoms with or without a spermicide

          -  Diaphragm or cervical cap with a spermicide

          -  Intrauterine device (IUD)

        If pregnancy is suspected or should occur, subjects must notify the study staff
        immediately.

        EXCLUSION CRITERIA:

        A subject will not be eligible to participate in the study if any of the following
        conditions are fulfilled at the time of enrollment:

          1. Life-threatening HES or other condition that, in the Investigator s opinion, places
             the subject at undue risk by participating in the study

          2. Pregnant or breast-feeding

          3. History of malignancy, including solid tumors and hematologic malignancies (except
             basal cell and squamous cell cancers of the skin that have been completely excised and
             cured)

          4. HIV infection or any other known immunodeficiency.

          5. Biopsy-proven eosinophilic granulomatosis with polyangiitis

          6. Positive test for FIP1L1/PDGFRA fusion gene

          7. Absolute neutrophil count <2000/microL at screening, or any documented history of
             neutropenia

          8. Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) of less
             than or equal to 80 mg/dL at screening (estimation of creatinine clearance using the
             MDRD formula).

          9. Cardiac abnormality defined as:

               1. Moderate to severely decreased cardiac function (left ventricular ejection
                  fraction (LVEF) < 20% or history of LVEF <20% within the past 6 months or NYHA
                  class IIIb or IV)

               2. History of angina or acute myocardial infarction in the past 6 months

               3. History or long QT syndrome or arrhythmia.

               4. A prolongation of QT/QTc interval (e.g., repeated demonstration of a QT/QTc
                  interval >450 ms before study treatment administration) at screening, admission
                  or pre-dose on Day 1.

               5. Any clinically important abnormalities in resting ECG that may interfere with the
                  interpretation of QTc interval changes at screening, admission or pre-dose on Day
                  1.

             This includes subjects with any of the following:

             i. PR interval >210 ms;

             ii. QRS >110 ms;

             iii. Heart rate <45 bpm or >100 bpm (average of 3 assessments).

         10. Recent history or suspicion of drug or alcohol abuse in the preceding 6 months

         11. Treatment with an investigational drug in the previous 30 days
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Amy D Klion, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02101138

Organization ID

140063

Secondary IDs

14-I-0063

Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

 Knopp Biosciences

Study Sponsor

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


Verification Date

December 1, 2017