Merck recommends that patients in the twice-daily dosing arms in these
studies be changed to a regimen with the approved dosing (800 mg every
eight hours) of Crixivan to ensure that they receive optimal therapy. Merck
continue to study twice-daily dosing of Crixivan in combination trials with other protease inhibitors.
The Company had initiated two studies to compare the antiviral efficacy
and tolerability of the approved 800 mg three-times daily dosing with twice-daily
dosing (1,200 mg every 12 hours) of Crixivan. The first study compared
Crixivan twice-daily versus Crixivan three-times daily, each in combination with the RTIs AZT(a) and 3TC(b), in patients starting antiretroviral therapy. The second, a transition study, evaluated the two dosing regimens (Crixivan twice-daily with RTIs and three-times daily with RTIs) among patients who had already achieved levels of virus below detection after six
months on therapy with the approved three-times daily dosing of Crixivan with RTIs.
The decision is based on data from an interim analysis of the initial therapy study at week 24 that showed that the three-times daily regimen was more effective than the twice-daily regimen in reducing levels of viral RNA to below detection (less than 400 copies/mL) in patients initiating therapy. At week 24, 91 percent of patients on the approved dosing regimen had achieved viral levels below 400 copies/mL, compared to 64 percent of patients on the twice-daily regimen.
"Although the initial therapy study provided us with additional evidence
of the potent antiviral effect of Crixivan dosed every eight hours
in combination with AZT and 3TC,'' explained Bach-Yen Nguyen, M.D., director,
Clinical Research, Merck Research Laboratories, ``the difference in efficacy between the two treatment arms over time indicates that the approved dosing regimen and the twice-daily dosing regimen are unlikely to reach equivalence.''
Crixivan in combination with other antiretroviral agents is indicated
for the treatment of HIV infection. Crixivan can help reduce the chance
of illnesses and death associated with HIV as demonstrated in clinical
trials of approximately one year. Patients currently on treatment with
Crixivan should continue to take their medication as prescribed by their
Physicians treating patients with Crixivan should consult the prescribing information.
Other Studies with Twice-Daily Crixivan Continue
Other studies now under way by Merck to evaluate the antiviral activity of twice-daily dosing of Crixivan combined with other protease inhibitors dosed twice-daily, such as nelfinavir and ritonavir, are continuing.
Potent Antiviral Effect Seen with Approved Dosing of Crixivan
The Merck studies were part of the Company's commitment to evaluate further the twice-daily dosing regimen in larger numbers of patients in an attempt to confirm encouraging antiviral results seen in a twice-daily dosing pilot study. Like the earlier pilot study, the larger twice-daily initial therapy study evaluated patients who had not received prior treatment with a protease inhibitor or 3TC. This study enrolled 635 patients. The transition study with 283 patients was designed to evaluate the two dosing regimens among patients who had achieved viral levels below the level of detection (<400 copies/mL) after six months on triple therapy with approved dosing (800 mg every eight hours) of Crixivan.
Analysis -- Initial Therapy Study
Efficacy results from the preliminary intent-to-treat analysis of the
initial therapy study were based on a total of 287 patients. At week 16,
78 percent of patients on the approved dosing regimen compared to 72 percent
the twice-daily regimen had viral load levels below 400 copies/mL. Among the 87 patients who had been followed in the study through 24 weeks, 91 percent of the group on the approved dosing regimen had viral load levels below 400
copies/mL, compared to 64 percent of the patients on the twice-daily arm. Patients enrolling in the study had CD4 counts greater than 100 cells/mm3 and viral RNA levels greater than 10,000 copies/mL. The study started in
November 1997 and was being conducted at 49 sites around the world.
Discontinuation rates were low and similar for both groups in the initial
treatment study, although there was a trend toward more discontinuations
due to nausea and vomiting in the twice-daily group compared to the approved-