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Press Release
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Boehringer Ingelheim Provides Update on Aptivus® (tipranavir) Clinical Trial in Treatment-Naïve HIV-Infected Patients
June 9, 2006 -- Boehringer Ingelheim is actively conducting a clinical trial program to further evaluate Aptivus® (tipranavir) capsules for the treatment of HIV-1 infection. The program is comprised of ongoing and planned studies in more than 1,000 patients with a spectrum of antiretroviral experience, including pediatric, racially and gender diverse, or hepatitis co-infected patients.
One of the studies in the clinical trial program, study 1182.33, was designed as a non-inferiority trial to evaluate the efficacy and safety of two doses of APTIVUS combined with ritonavir (500 mg/200 mg BID, 500 mg/100 mg BID) compared with lopinavir combined with ritonavir (400 mg/100 mg BID) in treatment-naïve HIV-infected patients, as part of combination antiretroviral treatment. The primary endpoint of this study is the proportion of treatment-naïve patients who have a confirmed viral load less than 50 copies/mL (treatment responders) at the time of their week 48 visit. Prior to study initiation, non-inferiority was defined to have been demonstrated if the upper or lower bound of the 97.5% confidence interval (CI) of the weighted differences in the proportion of treatment responders between either of the APTIVUS/ritonavir arms and the lopinavir/ritonavir arm did not exceed 15%.
Boehringer Ingelheim and the external independent Data Safety Monitoring Board (DSMB) conducted a thorough review of the 48-week data in February 2006. Data showed that the two APTIVUS/ritonavir arms (500 mg/100 mg and 500 mg/200 mg) achieved the primary study endpoint and were non-inferior to the comparator lopinavir/ritonavir arm. However, Boehringer Ingelheim, with the recommendation of the DSMB, closed the APTIVUS/ritonavir 500 mg/200 mg study arm because the rate of asymptomatic liver enzyme elevations reported in that arm was higher than in the other study arms and presented a less favorable benefit-risk profile for these treatment-naive patients. Boehringer Ingelheim and the DSMB supported the continuation of the APTIVUS/ritonavir 500 mg/100 mg and lopinavir/ritonavir study arms.
As part of the ongoing evaluation of study 1182.33, Boehringer Ingelheim recently conducted a post-hoc analysis when all patients had reached their week 60 visit (the subsequent visit to week 48). The APTIVUS/ritonavir 500 mg/100 mg arm was no longer non-inferior to the lopinavir/ritonavir arm (exact estimate: 15.03%). As a result, Boehringer Ingelheim, supported by the DSMB, has decided to close the trial. In contrast, the previously discontinued APTIVUS/ritonavir 500 mg/200 mg arm remained non-inferior to the lopinavir/ritonavir arm using the post-hoc analysis dataset.
The closure of this investigational treatment-naïve trial does not change the positive benefit-risk profile of APTIVUS/ritonavir at the approved dose (500 mg/200 mg twice daily) for its currently labeled indication. APTIVUS/ritonavir is approved for HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.
Boehringer Ingelheim study 1182.33 is a multinational study in 558 treatment-naïve patients conducted outside of the United States. It has clinical trial sites in Argentina, Australia, Bahamas, Brazil, Canada, Colombia, France, Germany, Mexico, Poland, Romania, Russia, Spain, Thailand and the UK.
Boehringer Ingelheim has informed regulatory authorities and 1182.33 study investigators about the trial closure and is committed to providing solutions for patients who do not have access to antiretroviral medications for the planned duration of the trial (156 weeks).
APTIVUS and Highly Treatment-Experienced Patients
APTIVUS/ritonavir is approved for combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. In this patient population, the approved dose of APTIVUS is 500 mg taken with 200 mg of ritonavir, twice daily. The accelerated approval of APTIVUS for treatment-experienced patients is based on 24-week data from the ongoing RESIST studies using surrogate endpoints, including changes in viral load and CD4 cell count. It was demonstrated that a significantly greater percentage of HIV-positive patients taking an APTIVUS/ritonavir-based regimen achieved a treatment response versus those taking a regimen containing one of several ritonavir-boosted comparator protease inhibitors.
Accelerated approval is a regulatory process that expedites the approval of therapies for serious or life-threatening illnesses that provide meaningful benefit to patients over existing treatments. The long-term effects of APTIVUS/ritonavir therapy are not confirmed at this time; however, Boehringer Ingelheim is evaluating longer term APTIVUS data from the RESIST studies to confirm the 24-week findings in highly treatment-experienced patients and complete the traditional approval package for submission to FDA.
The RESIST trials are randomized, controlled, open-label Phase 3 trials designed to study APTIVUS combined with ritonavir (APTIVUS/r) versus a group of ritonavir-boosted comparator protease inhibitors (CPI/r) in patients previously treated with all three classes of antiretroviral agents. Patients enrolled in the RESIST studies had received at least two previous PI-based regimens and were failing a PI-based regimen at the time of study entry. APTIVUS/r and the ritonavir-boosted comparator PIs were taken in conjunction with other anti-HIV agents as part of combination antiretroviral therapy. CPIs included lopinavir, saquinavir, amprenavir and indinavir. All patients had baseline genotypic resistance testing prior to randomization to aid investigators in the selection of the CPI/r. Of these highly treatment-experienced patients in the RESIST trials, the majority (86%) were at least possibly resistant to the CPI/r chosen.
Boehringer Ingelheim is committed to further studying APTIVUS capsules for the treatment of HIV-1 and improving therapy by discovering and developing innovative antiretroviral and anti-hepatitis C drugs.
For more information about APTIVUS please visit www.APTIVUS.com. APTIVUS clinical trial information is available on www.clinicaltrials.gov.