Protocol Number: 03-I-0021

Title:

Phase I/II Randomized, Double Blind, Dose Escalation Study of the Safety, Tolerability, Pharmacokinetics and Efficacy of Subcutaneous Bay 50-4798 Admn in Pts with HIV Infection on Highly Active Antiretroviral Therapy (HAART) Compared to Pts on HAART Alone

Number:

03-I-0021

Summary:

This test will evaluate the safety of the experimental drug Bay 50-4798 in HIV-infected patients and determine the highest dose of the drug that can be given without producing serious side effects. It will also examine the drug's effect on CD4+ T-cell counts.

The immune system of patients with HIV infection do not produce enough interleukin-2 (IL-2), a substance that helps activate CD4+ cells to respond to various infections, including HIV. The drug Proleukin® (Registered Trademark) acts the same way in the body as IL-2 and has helped to increase CD4+ T-cells in HIV-infected patients. However, Proleukin® (Registered Trademark) causes some serious side effects, perhaps because of its stimulation of various immune system cells. Bay 50-4798 is similar to IL-2 and to Proleukin, but may not stimulate the immune system to produce the adverse effects of Proleukin® (Registered Trademark).

HIV-infected patients 18 years of age and older may be eligible for this study. Candidates must have fewer than 10,000 copies/ml of virus on at least two occasions within 8 weeks of entering the study and no more than a 0.5 log increase between the most recent and the earlier viral load measurements. Their CD4+ T-cell count must be at least 200/mm3 on at least two occasions within 8 weeks of study entry. They must be on a stable HAART (highly active antiretroviral therapy) regimen and not have had prior treatment with IL-2 or similar drug. Candidates will be screened with a medical history and physical examination, blood and urine tests, an echocardiogram (ultrasound tests to assess pumping strength of the heart), electrocardiogram, or ECG (to record the electrical activity of the heart), and possibly questionnaires to measure fatigue.

Participants will be randomly assigned to take HAART therapy alone or to take HAART plus Bay 50-4798. Three out of four patients will receive Bay 50-4798, which is given as an injection under the skin. The dose of drug will also be randomly assigned among those taking it, ranging from 2.6 micrograms per kilogram (2.2 pounds) of body weight to 15.5 mcg/kg body weight. The rest of the patients will receive placebo (an inactive substance), also injected under the skin. Treatment will be given in three 8-week cycles. Each cycle includes a pre-treatment visit, then 5 consecutive days of drug or placebo, then 1 day of medical evaluation and a post-treatment visit 1 month from the start of the cycle. Patients will also have an end-of-study evaluation following the last treatment cycle.

Medical evaluations may include a check of vital signs, weight measurement, ECG, urine and blood tests, a history of symptoms since the previous visit, and questionnaires regarding level of fatigue, if any. On days 1 and 5 of the first cycle, blood will be taken several times over the course of the day to measure blood levels of Bay 50-4798 and examine its effects on the immune system.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Documented HIV infection (positive enzyme linked immuno assay (EIA) confirmed by Western Blot).

Age greater than or equal to 18 years.

Plasma HIV VL less than 10,000 copies/ml (by bDNA assay or RT-PCR) on at least 2 occasions at least 4 weeks apart but no more than 8 weeks prior to screening with no more than a 0.5 log increase between the most recent and the earlier VL measurements.

CD4 (+) T-cell count greater than or equal to 200/mm(3) on at least 2 occasions within 8 weeks of study entry.

On a stable HAART regimen for greater than or equal to 8 weeks.

Karnoffsky Score greater than or equal to 80.

Written informed consent.

Sexually active patients must use a barrier method of contraception.

EXCLUSION CRITERIA:

Prior treatment with IL-2 or an IL-2 analogue.

Pregnancy or breastfeeding.

Use of any known immunomodulators, cytokines, growth factors or systemic corticosteroids (e.g. prednisone greater than or equal to 15 mg QD or equivalent) within 4 weeks prior to study enrollment.

History of an AIDS defining illness by the Centers for Disease Control (CDC) definition within 8 weeks prior to study entry.

Acute bacterial or viral infection within 4 weeks prior to enrollment.

Received an immunization within 4 weeks prior to enrollment.

History of autoimmune disease including psoriasis, inflammatory bowel disease.

Medical history of transplantation (solid organ or bone marrow).

Received an investigational drug in the past 30 days other than Food and Drug Administration (FDA) sanctioned treatment IND antiretroviral agents.

Renal insufficiency with a serum Creatinine level greater than 1.5 times the upper limit of normal (ULN).

Bone marrow suppression as defined by one or more of the following:

Granulocyte count less than 1,000/mm(3)

Hemoglobin less than 9.0g (females) or less than 9.5g (males)

Platelet count less than 75,000/mm(3)

Evidence of hepatic disease indicated by one or more of the following:

SGOT (AST) and/or SGPT (ALT) greater than 5 times the upper limit of normal.

Bilirubin greater than 2 times the upper limit of normal (except for patients with known Gilbert's syndrome or those receiving indinavir who may be enrolled if the serum bilirubin is less than or equal to 5 times the upper limit of normal).

Active cardiac disease (coronary artery disease, congestive heart failure or cardiomyopathy) requiring treatment with any of the following medications: antiarrhythmic agents including digitalis, anti-anginal drugs including topical or systemic nitrates, calcium channel blockers, and beta blockers, and afterload reducers including ACE inhibitors. Patients requiring any of these medications solely for the treatment of hypertension remain eligible for the study.

Presence of significant cardiac insufficiency (greater than or equal to New York Heart Association Grade 2).

Diagnosis of an active malignancy requiring treatment with systemic cytotoxic chemotherapy.

Active alcohol or substance abuse which, in the opinion of the investigator, will seriously compromise the subject's ability to adhere with the demands of the study.

Any central nervous system (CNS) disease that requires active treatment with anticonvulsants.

Use of an antimetabolite such as hydroxyurea within 4 weeks prior to study entry.

Known co-infection with Hepatitis B or C virus unless serum transaminases are less than or equal to 2 times the upper limit of normal on at least two occasions within 8 weeks prior to study entry.

Known CD4 Nadir less than 50 cells/mm(3).

Special Instructions: Currently Not Provided

Keywords:

IL-2

Immunomodulator

CD4 Cells

Selective Agonist

Cytokine

Recruitment Keywords:

HIV

Conditions:

HIV Infections

Investigational Drug(s):

Bay 50-4798

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:

Lalezari JP, Beal JA, Ruane PJ, Cohen CJ, Jacobson EL, Sundin D, Leong WP, Raffanti SP, Wheeler DA, Anderson RD, Keiser P, Schrader SR, Goodgame JC, Steinhart CR, Murphy RL, Wolin MJ, Smith KA. Low-dose daily subcutaneous interleukin-2 in combination with highly active antiretroviral therapy in HIV+ patients: a randomized controlled trial. HIV Clin Trials. 2000 Nov-Dec;1(3):1-15. PMID: 11590500

Witzke O, Winterhagen T, Reinhardt W, Heemann U, Grosse-Wilde H, Kreuzfelder E, Roggendorf M, Philipp T. Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease. J Intern Med. 1998 Sep;244(3):235-40. PMID: 9747746

Carr A, Emery S, Lloyd A, Hoy J, Garsia R, French M, Stewart G, Fyfe G, Cooper DA. Outpatient continuous intravenous interleukin-2 or subcutaneous, polyethylene glycol-modified interleukin-2 in human immunodeficiency virus-infected patients: a randomized, controlled, multicenter study. Australian IL-2 tudy Group. J Infect Dis. 1998 Oct;178(4):992-9. PMID: 9806026

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