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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Collaborator:
Knopp Biosciences
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT02101138
First received: March 14, 2014
Last updated: September 13, 2014
Last verified: February 2014
  Purpose

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.

Condition Intervention Phase
Hypereosinophilic Syndrome
Drug: Dexpramipexole
Drug: Corticosteroid Taper
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Proof-of-Concept Study to Evaluate the Safety and Efficacy of Dexpramipexole (KNS-760704) in Subjects With Hypereosinophilic Syndrome

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • A binary response indicating whether or not the subject had a greater than or equal to 50 % change in prednisone dose to maintain AEC & lt; 1000/microL and control clinical symptoms and 2) the change in minimal effective corticosteroid dose... [ Time Frame: 3-6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Reduction in circulating eosinophils after 3 months of treatment with dexpramipexole (prior to steroid taper) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • Reduction in bone marrow eosinophils and myeloid precursors after 3 months of treatment with dexpramipexole (prior to steroid taper) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  • Number of subjects able to taper to & lt; 10 mg prednisone and maintain AEC& lt; 1000/microL and control of clinical symptoms [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  • Incidence and severity of adverse events [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 15
Study Start Date: February 2014
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Dexpramipexole
    N/A
    Drug: Corticosteroid Taper
    N/A
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 amino-benzothiazole 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 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. Once this is established, treatment with dexpramipexole 150 mg twice daily will begin. A second standardized corticosteroid taper will begin after 12 weeks of treatment with dexpramipexole. The minimally effective corticosteroid dose on dexpramipexole will be determined. 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 50 % change in prednisone (or equivalent) dose to maintain absolute eosinophil count (AEC) < 1000/microL 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 one-sided 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 controlled and the subject has an AEC < 1000/microL 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02101138

Contacts
Contact: Tamika S Magee, R.N. (301) 443-5458 mageets@mail.nih.gov
Contact: Amy D Klion, M.D. (301) 435-8903 aklion@niaid.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Knopp Biosciences
Investigators
Principal Investigator: Amy D Klion, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT02101138     History of Changes
Other Study ID Numbers: 140063, 14-I-0063
Study First Received: March 14, 2014
Last Updated: September 13, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Corticosteroids
Eosinophilia

Additional relevant MeSH terms:
Syndrome
Hypereosinophilic Syndrome
Disease
Pathologic Processes
Eosinophilia
Leukocyte Disorders
Hematologic Diseases
Pramipexole
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Dopamine Agonists
Dopamine Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on October 19, 2014