Protocol Number: 04-I-0158

Title:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Phase III Study to Evaluate Corticosteroid-Reduction and -Sparing Effects of Mepolizumab 750 mg Intravenous in Subjects with Hypereosinophilic Syndromes (HES), and to evaluate the

Number:

04-I-0158

Summary:

This study will examine the safety and effectiveness of the drug mepolizumab for treating patients with hypereosinophilic syndrome (HES), a disease in which patients have too many eosinophils (a type of white blood cell) in the blood and in body tissues. This causes damage to affected organs, most commonly the heart, nerves and skin. Mepolizumab is a genetically engineered antibody to interleukin 5, a hormone-like substance produced by white blood cells that plays a significant role in eosinophilia.

Patients with HES between 18 and 75 years of age may be eligible for this study. Candidates are screened with a medical history, physical examination, electrocardiogram, and blood tests.

Participants are treated with prednisone or another corticosteroid for 1 to 6 weeks while they gradually stop taking all other medications for HES. Patients whose disease is controlled successfully with 20 to 50 mg of prednisone a day (or the equivalent) for 1 week may continue in the study. They undergo a baseline evaluation, including physical, neurological and skin exams, a skin biopsy if skin lesions are present, blood and urine tests, electrocardiogram (ECG), echocardiogram, esophagogastroduodenoscopy (EGD, a procedure in which a tube-like instrument is advanced from the throat to the upper part of the gut to examine the gastrointestinal tract), CT scans of the sinuses, lungs, and abdomen, and quality of life assessments.

Patients are then randomly assigned to receive an infusion by vein every 4 weeks of either mepolizumab or placebo (a substance that contains no active drug) for 36 weeks. One week after beginning the study drug, patients' prednisone dose is gradually reduced until it is stopped. Patients are followed weekly for the first 12 weeks by NIH physicians or by the patient's local physician as well as every 4 weeks throughout the study at NIH until treatment is complete. Patients undergo the following tests and procedures during the treatment period:

- History, physical examination, and skin assessments: every 4 weeks.

- Neurologic exam: weeks 4, 8, 16, and 36 (or at the patient's final visit if earlier than 36 weeks).

- Blood tests: chemistries and hematology every week for 12 weeks and then every 4 weeks until the end of the study; measurements of mepolizumab levels at weeks 1, 2, 3, 4, 8, 16, 24, 32 and the end of the study; tests to detect antibodies against mepolizumab every 12 weeks.

- ECG: every 8 weeks.

- Echocardiogram and lung function tests: week 16 and the end of the study.

- CT scans of parts of the body affected by HES: at the end of the study.

- EGD: week 16 and the end of the study if there are gastrointestinal signs and symptoms thought to be related to HES.

- Urine collection: every 4 weeks for pregnancy test in women of childbearing potential; urinalysis at week 12 and the end of the study.

- Questionnaires to assess physical and mental condition: every 12 weeks

During the study, patients' symptoms are treated with prednisone or another corticosteroid. Those who require other medications to control symptoms are taken off the study. Patients are contacted three months after their last dose of drug upon completing or withdrawing from the study to check on possible adverse events and for a final urine pregnancy test in women.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

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

Signed informed consent.

Subjects with documented history of HES.

-HES is defined as: 1) peripheral blood eosinophilia (greater than 1500 eosinophils/micro L) for at least 6 months, 2) signs and symptoms of organ system involvement or dysfunction that can be directly related to eosinophilia, 3) no evidence of parasitic, allergic, or other recognized causes of eosinophilia after comprehensive evaluation.

-Subjects with sustained peripheral hypereosinophilia of greater than 1500 eosinophils/micro L for a duration of less than 6 months may be included if they meet the rest of the HES criteria accompanied by clear evidence of eosinophil tissue infiltration.

Subjects must achieve and maintain a stable prednisone monotherapy status prior to randomization. A stable prednisone monotherapy status is defined as:

-No new or worsening HES clinical signs and symptoms with a blood eosinophil count less than 1000/micro L when treated with prednisone monotherapy at a stable daily dose of greater than or equal to 20 mg to less than or equal to 50 mg for a minimum of one week.

Subjects must complete all the screening/baseline assessments as outlined in the protocol.

Male or female, 18-75 years of age. A female subject is eligible to enter the study if she is:

-Not pregnant or nursing;

-Of non-childbearing potential (i.e., women who had a hysterectomy, are post-menopausal which is defined as 1 year without menses, have both ovaries surgically removed, or have current documented tubule ligation); or

-Of childbearing potential (i.e., women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea (even severe), women who are perimenopausal or have just begun to menstruate. These women must have a negative serum pregnancy test at the Screening Visit, and agree to one of the following: 1) Complete abstinence from intercourse for 2 weeks prior to administration of the first dose of investigational product until 3 months after the last dose of investigational product; OR 2) Consistent and correct use of one of the following acceptable methods of birth control for one month prior to the start of the investigation product and three months after the last dose:

-Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for the female subjects;

-Implants of levonorgestrel;

-Injectable progestogen;

-Any intrauterine device (IUD) with a documented failure rate of less than 1% per year;

-Oral contraceptives (either combined or progestogen only).

-Double-barrier methods including diaphragm or condom with a spermicide.

EXCLUSION CRITERIA:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

Subjects with life-threatening or other serious illness or clinical manifestation deemed inappropriate for inclusion in study per the principal investigator.

Known secondary causes of eosinophilia: drug eruption and parasitic infection occurred within a year prior to the Screening Visit, with a history of severe allergic disease, cystic fibrosis, graft-versus host disease, bullous pemphigoid, rheumatoid arthritis and human immunodeficiency virus (HIV) infection.

Known Churg-Strauss Syndrome.

Known Wegener's Granulomatosis.

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

Abnormal laboratory value of:

-Serum creatinine greater than or equal to 3 times institutional upper limit normal (ULN);

-AST or/ALT greater than or equal to 5 times institutional ULN;

-Platelet count less than 50,000/micro L.

Cardiac function as the following:

-Left ventricular ejection fraction (LVEF) less than 20%. (Subject with a history of LVEF less than 20% within 6 months prior to screening should also be excluded);

-NYHA class IIIb or IV;

-Angina or acute myocardial infarction.

Known history of allergic reaction to previous antibody therapy.

Prior treatment with an anti-hIL-5 monoclonal antibody.

Use of an investigational drug within 30 days of entering the study (Screening Visit).

Recent history or suspicion of current drug abuse or alcohol abuse within the last 6 months.

Positive serum pregnancy test at the Screening Visit or urine pregnancy test at Baseline Visit.

Test positive for FIP1L1-PDGFR alpha fusion gene.

Special Instructions: Currently Not Provided

Keywords:

Eosinophil

Monoclonal Antibody

Treatment

Recruitment Keywords:

Eosinophil

Hyperesosinophilic Syndrome

HES

Conditions:

Hypereosinophilic Syndrome

Investigational Drug(s):

SB-240563 (mepolizumab)

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Cardon LR, et al. Testing drug response in the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics. 2000 Aug;10(6):503-10. PMID: 10975604

Arranz M, et al. Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet. 1995 Jul 29;346(8970):281-2. PMID: 7630250

Daly AK. Molecular basis of polymorphic drug metabolism. J Mol Med. 1995 Nov;73(11):539-53. Review. PMID: 8751138

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