GW873140 to Treat HIV-1 Infected Adults
This study will determine which of four doses of GW873140 can safely be given to adults to lower the amount of virus (HIV-1) in the body. GW873140 is a new type of anti-HIV drug called a CCR5 receptor antagonist. CCR5 is a receptor on T cells (a type of white blood cell) where HIV-1 enters and then infects the cell. GW873140 is intended to block the CCR5 receptor so that HIV-1 cannot enter the cell.
HIV-1-infected patients 18 years of age and older may be eligible for this study. Candidates are screened with a medical history and physical examination, electrocardiogram, and blood and urine tests. Some of the blood drawn is used to test the patient's HIV-1 type to see if the study drug might lower the amount of HIV-1 in the blood. Women who can become pregnant have a pregnancy test.
Participants are hospitalized for 12 days. They are randomly assigned to take one of the following four treatments for 10 days: 1) 200 mg of GW873140 once a day, or placebo (a look-alike pill with no active ingredient); 2) 200 mg of GW873140 twice a day, or placebo; 3) 400 mg of GW873140 once a day, or placebo; or 600 mg of GW873140 twice a day, or placebo. Participants record the meals they eat on a diary card. In addition, they undergo the following tests and procedures:
- Assessment of HIV classification (day 1)
- Review of meal diary cards (days 1,2,3,4,5,8, and 10)
- Review of any HIV-associated conditions, other medications taken besides the study drug, and well-being (days 1,2,3,4,5,8,10, and 11)
- Check of vital signs, including blood pressure, pulse, and temperature (days 1,2,3,4,5,6,7,8,10, and 11)
- Weight assessment (days 1 and 10)
- Electrocardiogram to measure the electrical activity of the heart (days 1,2,3,8, and 10)
- Blood draws for routine laboratory tests, to measure T-cell counts, and to measure HIV levels (days 1,2,5,10, and 11)
- Urine tests (days 1 and 10)
- Blood tests to monitor the effect of GW873140 on lowering HIV counts (days 12, 15, 17, and 19)
Follow-up visit (2 weeks after last drug dose--day 24)
- Review of medications taken and general well-being
- Check of vital signs
- Physical examination
- Blood and urine tests.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Primary Purpose: Treatment
|Official Title:||A Phase II, Double-Blind RAndomized, Placebo-Controlled Study to Evaluate the Antiviral Activity, Safety, Tolerability, and Pharmacokinetics of GW873130 for 10 Days in HIV-1 Infected Adults|
|Study Start Date:||January 2004|
|Estimated Study Completion Date:||March 2005|
The development of resistance to all currently marketed drugs for HIV infection has been observed and is a major reason for failure of therapy. In particular, there is a great need for drugs against new targets and having novel mechanisms of action against new targets. Most of the currently approved drugs are targeted toward the inhibition of viral enzymes. However, the process of viral entry and fusion has become an active area of research. Among the steps involved in viral entry, binding of HIV to CD4 co-receptors on the cell surface is an important and promising target for new drug development.
GW873140 is a CCR5 antagonist that is in Phase I clinical development as a viral entry inhibitor for the treatment of HIV infection. GW873140 has demonstrated in vitro antiviral activity with an IC50 against CCR5-tropic HIV-1 of 1nM equals about 0.5ng/mL), that is shifted 8-10 fold (10nM equals about 0.5ng/mL) in the presence of physiological concentrations of human plasma proteins. A study to investigate the safety, tolerability, and pharmacokinetics of escalating single (50-1200mg) and repeat (200-800mg BID) doses of GW873140 has been conducted in 70 healthy volunteers (GW873140/001). Preliminary results indicate that GW873140 is well-tolerated up to a dose of 1200 mg following single dose and 800 mg BID following multiple-dose. Additionally, food was shown to increase the AUC and Cmax of a 400 mg single dose by 1.7-and 2.2-fold, respectively.
Concentrations above the protein binding corrected IC90 are achieved following oral dosing and in vivo binding studies in healthy subjects demonstrate greater than 97% receptor occupancy 2 and 12 hours after multiple doses and 68-88% receptor occupancy 24 hours after a single dose, despite plasma concentrations below or near detectable limits.
|United States, Maryland|
|National Institute of Allergy and Infectious Diseases (NIAID)|
|Bethesda, Maryland, United States, 20892|