September 28, 2006
GRACE (Gender, Race And Clinical Experience), a multi-center, open-label Phase IIIb trial, will compare gender differences in the efficacy, safety and tolerability of Prezista (darunavir) tablets administered with other antiretroviral agents over a 48-week treatment period. The study also will explore racial differences in treatment outcomes.
Prezista, co-administered with 100 mg ritonavir (Prezista/rtv) and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor. Prezista received accelerated approval based on the 24-week analysis of HIV viral load and CD4+ cell counts from the pooled analysis of the TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2) studies. Longer-term data will be required before the FDA can consider traditional approval for Prezista (see the full indication and important safety information below).
There is an urgent need to conduct clinical trials designed specifically for women with HIV. The ratio of women to men among Americans diagnosed with HIV has grown substantially since the HIV epidemic first emerged.
"GRACE is a landmark study because HIV treatment trials -- including those looking at treatment-experienced populations -- have traditionally included very small numbers of women, especially in the earliest studies of new antiretroviral agents. We know that there are gender-specific complications associated with HIV disease. However, we do not know a great deal about how gender impacts the efficacy and side effects of HIV medications," said Judith Currier, M.D., Associate Director of the University of California, Los Angeles, Center for Clinical AIDS Research and Education and a lead investigator in the GRACE study.
"The need for an increased focus on women living with HIV/AIDS was a key theme of the recent AIDS 2006 conference in Toronto, Canada. GRACE is an example of the steps that need to be taken to address the evolving HIV epidemic. The development of this trial included extensive collaboration with the HIV community," said Dawn Averitt-Bridge, founder and Chair of the Board of The Well Project. "Women who participate in GRACE will play a very important role in advancing the understanding of HIV treatment in women."
The GRACE study will include approximately 50 sites in the United States, Mexico and Canada, and will seek to enroll approximately 420 participants, 70 percent of whom will be women. Participants must be of 18 years or older, have a viral load of 1000 copies/mL or greater and have previous intolerance or failure to prior therapy consisting of a protease inhibitor and/or non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral treatment regimen of at least 12 weeks. All participants will receive Prezista/rtv (600/100mg twice a day) with an optimized background regimen chosen by the investigator and based on resistance testing and prior treatment history.
This indication is based on Week 24 analyses of plasma HIV RNA levels and CD4+ cell counts from two controlled trials of Prezista/rtv in combination with other antiretroviral drugs. Both studies were conducted in clinically advanced, treatment-experienced (NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with Prezista/rtv:
Coadministration of Prezista/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and have a narrow therapeutic index (e.g., astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, or triazolam) and for which elevated plasma concentrations are associated with serious and/or life-threatening events.1 Coadministration is not recommended with carbamazepine, phenobarbital, phenytoin, rifampin, lopinavir/ritonavir, saquinavir, lovastatin, pravastatin, simvastatin, or products containing St. John's wort (Hypericum perforatum).
Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A in patients receiving Prezista/rtv. This list of potential drug interactions is not complete.
Prezista must be co-administered with 100 mg ritonavir and food to exert its therapeutic effect. Failure to correctly administer Prezista with ritonavir and food will result in reduced plasma concentration of darunavir that will be insufficient to achieve the desired antiviral effect. Please refer to ritonavir prescribing information for additional information on precautionary measures.
Severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported in subjects receiving Prezista during the clinical development program. In some cases, fever and elevations of transanimases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in seven percent of subjects treated with Prezista; discontinuation due to rash was 0.3 percent. Rashes were generally mild-to-moderate, self-limiting and maculopapular. Prezista should be discontinued if severe rash develops.
Prezista should be used with caution in patients with known sulfonamide allergy.
New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.
Prezista should be used with caution in patients with hepatic impairment. There are no data regarding the use of Prezista in patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made.
Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.
Immune reconstitution syndrome has been reported in patients treated with ARV therapy.
The potential for HIV-cross-resistance among protease inhibitors has not been fully explored in Prezista/rtv treated patients.
Prezista should be used during pregnancy only if the potential benefit justifies the potential risk. There are no adequate and well-controlled studies in pregnant women. The effects of Prezista on pregnant women or their unborn babies are not known.
In the pooled analysis of POWER 1 and 2 studies, the most frequently reported drug-related adverse events of at least moderate to severe intensity in patients receiving Prezista/rtv-containing regimen were headache (3.8 percent), diarrhea (2.3 percent), abdominal pain (2.3 percent), constipation (2.3 percent), and vomiting (1.5 percent).
Please see full Prescribing Information for more details.
An application for marketing authorization was filed with the European Agency for the Evaluation of Medicinal Products (EMEA) in January 2006. Applications for approval have also been submitted or are planned for submission in several other countries around the world in the coming months. Following regulatory approval, Tibotec, a division of Janssen-Cilag, will commercialize Prezista in Europe and other countries; Tibotec, a division of Janssen-Ortho Inc., is commercializing Prezista in Canada.
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