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DAPD + Fuzeon Pilot Study: ACTG 5118
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"A Randomized, Placebo-controlled Trial of Amdoxovir vs Placebo with Enfuvirtide plus Optimized Background Therapy for HIV-infected Subjects Failing Current Therapy (AACTG 5118)"
12th CROI poster abstract 553.
Barbara Gripshover*1, J Santana2, H Ribaudo3, J Gerber4, C Thomas5, E Hogg6, B Jarocki7, S Hammer8, and D Kuritzkes9
1Univ Hosp of Cleveland, Case Western Reserve Univ, OH, USA; 2Univ of Puerto Rico Sch of Med, San Juan; 3Harvard Sch of Publ Hlth, Boston, MA, USA; 4Univ of Colorado Hlth Sci Ctr, Denver, USA; 5Univ of Colorado Hlth Sci Ctr, Denver, USA; 6ACTG Operations Office, Silver Spring, MD, USA; 7Frontier Sci & Tech Res Fndn, Amherst, NY, USA; 8Columbia Presbyterian Med Ctr, New York, NY, USA; and 9Brigham & Women's Hosp, Harvard Med Sch, Boston, MA, USA
Background: Cross resistance limits the ability to construct effective antiretroviral regimens for persons failing current therapies. A5118 compared the use of amdoxovir (DAPD), a novel nucleoside analog to placebo in combination with enfuvirtide (ENF) plus optimized background therapy (OBT) in ENF-naïve subjects who had failed ≥ 2 antiretroviral (ARV) regimens including at least 2 nucleoside reverse transcriptase inhibitors (NRTI), 2 protease inhibitors (PI), and 1 non-NRTI (NNRTI).
Methods: This randomized, prospective, double-blind, placebo-controlled study assessed the antiretroviral activity and safety of DAPD (300 mg by mouth twice a day) vs placebo with ENF (90 mg subcutaneously twice a day) plus OBT (3 to 5 agents selected based on genotypic and phenotypic testing at screening) in subjects described above. The primary endpoints were comparison between arms of time-averaged area under the curve minus baseline in plasma HIV RNA copies/mL (copies/mL) at 24 week and time to first serious (AACTG ≥ grade 3 or 4) adverse event. Planned sample size was 50 subjects, however study enrollment was terminated following an unplanned interim review convened when the long-term development plans for DAPD became uncertain. Subjects on study were unblinded and allowed to continue through 48 week; 24 week data on the 18 subjects (9 per arm) enrolled are reported here.
Results: Median baseline CD4 cell count was 36 cells/mm3 (range, 11 to 537); HIV RNA was 4.8 log10 copies/mL (range, 3.5 to 6.3). Baseline samples showed a median of 6 NRTI mutations and 8 PI mutations; NNRTI resistance was present in samples from 13 of 18 subjects: 4 subjects discontinued therapy prior to week 24; 3 for poor virologic response (2 on DAPD; 1 on placebo); 1 subject on placebo discontinued for ENF injection site reactions; 2 subjects (one per arm) briefly interrupted therapy for decreased creatinine clearance. By intention-to-treat analysis, the of time-averaged area under the curve minus baseline was -1.1 log10 copies/mL (95% CI = 0.19 to 2.01) in the DAPD arm and -0.8 log10 copies/mL (95% CI = 0.15 to 1.45) in the placebo arm (p = 0.69). Mean CD4 increase was 70 cells/mm3 (95% CI = 35 to 105) in the DAPD arm and 54 (95% CI = 14 to 94) in the placebo arm (p = 0.45). Time to first serious adverse event did not differ between arms. ENF injection site reactions were the most common adverse events (5 subjects). Mild decreases in creatinine clearance were equal between arms, and no subject developed an increase in lens opacity score.
Conclusions: In this pilot study, the addition of DAPD to ENF with optimized background therapy in advanced and highly resistant subjects appeared safe. Further studies of DAPD in this setting are warranted.
In animal & human studies of DAPD researchers have found a potential association between DAPD and a toxicity called Ôlens opacitiesÕ. The association appears uncertain and the development of the drug appears uncertain. Here is the report of the study in patients finding a potential association.
Preliminary Results of Dosing of Amdoxovir in Treatment-experienced Patients.
Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th:
abstract no. 554
Thompson M, Richmond G, Kessler H, Bae A, Sorbel J, Sista N, Adda N, Rousseau F; Atlanta, GA
BACKGROUND: Amdoxovir (DAPD), a dioxalane guanosine analog, and its deaminated metabolite DXG are nucleoside reverse transcriptase inhibitors (NRTIs). DAPD 150 is a 96-week study designed to evaluate the long-term safety, tolerability, and antiviral activity of DAPD.
METHODS: In an on-going nonrandomized, open-label, Phase I/II study, a total of 18 HIV-infected, treatment-experienced subjects were randomized to receive either 300 mg BID or 500 mg BID DAPD in addition to their background regimen that could be optimized at the discretion of the investigator.
RESULTS: Subjects were treatment experienced with a median duration of 8 years of exposure to a median of 10 ART drugs and with a median of 5 NRTI mutations. The median duration of treatment in patients (pts) receiving at least one dose of DAPD is 16.8 weeks. The table below shows the preliminary results at week 12 of the study. DAPD was well tolerated across both dose groups. There were no deaths, SAEs, or dose-related trends in adverse events. No serum creatinine or glucose elevations above grade 1 or abnormal urinalysis results were reported. There were no treatment-emergent Grade 3 or 4 laboratory toxicities except for triglycerides in one pt in each dose group. Ten pts discontinued the study: 2 due to VF, 3 for non-compliance with the protocol, and 5 for presence of lens opacities which did not impact visual acuity.
CONCLUSIONS: Preliminary results suggest antiviral activity and tolerability of DAPD in treatment-experienced subjects and warrant further studies.
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