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Raltegravir FDA Clinical Development Summary
  This NDA contains clinical data collected primarily from four clinical studies, including the two pivotal studies Protocol 018 and Protocol 019. Protocols 018 and 019 are international, multi-center, double-blind, randomized, placebo-controlled trials comparing raltegravir in combination with optimized background therapy (OBT) to OBT alone in highly treatment-experienced HIV-infected subjects. The studies were identical except for the location of the study sites. Protocol 018 was conducted in Europe, Asia/Pacific, and South America, while Protocol 019 was conducted in North and South America. Eligible subjects were HIV-1 infected patients who had failed therapy as documented by HIV RNA >1,000 copies/mL while on stable therapy and documented resistance to at least 1 drug in each of 3 classes of licensed oral ARVs (NNRTI, NRTI, and PI).
Several supportive studies were also submitted, including Protocol 004, a dose-finding study in treatment-naive patients and Protocol 005, a dose-finding study in treatment-experienced patients that evaluated doses of 200 mg, 400 mg, and 600 mg of raltegravir versus OBT for 48 weeks. Dose selection for Phase 3 was based on Week 24 study data. A pediatric study is currently underway, but no pediatric data were submitted in support of this NDA. Other ongoing studies include expanded access Protocol 023 and a large Phase 3 trial in treatment-naive patients, Protocol 021.
TABLE 3 - Week 24 Outcomes
At week 24 (protocol 18), 76% <400 in Raltegravir+OBT arm, 41% in placebo+OBT; 60% <50 in RALT+OBT+OBT. Week 16 nonresponder: 2% RALT, 37% placebo; week 24 rebound: 13% RALT, 16% placebo (protocol 19 had similar results).



1PSS score was defined as the total oral ARVs in OBT to which a patient's viral isolate showed phenotypic sensitivity based on phenotypic resistance test. Enfuvirtide use in OBT in enfuvirtide-naive patients was counted as one active drug in OBT and added to the PSS. Darunavir use in OBT in darunavir-naive patients was counted as one active drug in OBT and added to the PSS.
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