NATAP
REPORTS
January 1998 Volume 1, Number 3-4 section 3
CNAA2001: 1592 Study for Treatment Naive Individuals. This study was for individuals with less than 12 weeks prior experience with AZT and CD4 cell counts between 200 to 500. 80 patients were randomized to one of four dose regimens of 1592.
The study was not designed to determine efficacy.
All patients received 4 weeks of 1592 monotherapy at the dose to which they were randomized. After 4 weeks, individuals were randomized to receive 1592+AZT or 1592+placebo for an additional 8 weeks. There was about a 2 log reduction at week 12 for all the arms (n=15 to 20 individuals per arm). At week 12, about 65% of the individuals who received 1592+AZT were undetectable (<400 copies/ml) while 22% receiving 1592 monotherapy were <400 copies/ml. The CD4 increases ranged from about 70 to 100 cells.
Participants in CNAA 2001, described above, were required to stop study medications after 12 weeks. 9 individuals from CNAA 2001 participated in a continuation study and received a triple regimen consisting of 1592 300 mg bid, AZT or 3TC, and indinavir or ritonavir.
The preliminary data for 8 participants were reported in Hamburg:
• Baseline HIV RNA (sensitivity limit of 400 copies/ml) was 4.54 log (about 35,000 copies/ml), n-9; after 24 weeks the average viral load reduction was -2.60 log (n-8).
• Baseline CD4 count was 315 cells; after 24 weeks the average CD4 count was 489 (n=8).
No patients discontinued 1592 due to an adverse event. The most commonly reported adverse events were nausea and diarrhea which resolved either spontaneously or upon therapy change. No serious adverse events were observed.
See the Resistance Supplement for CNAA 2003 in Nucleoside Experienced Individuals and for 1592 Resistance information.
CNAB 2002: 1592 Dose Ranging Study: 44 weeks. 60 treatment naive individuals with HIV RNA =30,000 copies/ml and CD4 counts =100 cells were randomized to 1592 doses of 100, 300 or 600 mg twice daily (BID). This study was designed to select a dose for future studies, not to measure efficacy. Participants who met switch criteria (<0.7 log decrease at week 4, =5,000 copies/ml after week 4, CD4 count return to baseline, or the occurrence of an AIDS defining event), had the option to switch to open-label 1592 300 mg bid+AZT/3TC. This study was designed to select a dose, not to determine efficacy.
At week 4, all doses showed an antiviral effect by a reduction in HIV RNA:
• 100 mg bid, -0.63 log
(-0.52 to -1.54)
• 300 mg bid, -1.55 log (-0.1 to -2.76)
• 600 mg bid, -1.61 log (-0.52 to -2.32)
<0.7 log reduction:
• 9/20 in the 100 mg arm
• 5/20 in the 300 mg arm
• 5/20 in the 600 mg arm
Investigators concluded 300 and 600 mg twice daily doses were superior. 2/20 (10%) and 5/19 (26%) had HIV RNA <400 copies/ml at week 4 in the 300 and 600 mg arms, respectively. The investigators characterized the drug as well tolerated. There were 5 withdrawals before week 24: 4 due to adverse events; 1 lost to follow-up.
For those individuals who added 1592 to AZT/3TC they achieved about a 2 to 2.5 log reduction which was maintained out to 44 weeks. At 24 weeks the N (number of evaluable patients) was 27, at week 36 the N was 6, and at week 44 the N was 3. More than 50 of the original 60 participants are still in the study. Glaxo Wellcome is conducting pediatric studies for 1592. Application for FDA approval for both adult and pediatrics should be submitted together.