June 9, 2006
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-naive HIV-infected patients, as part of combination antiretroviral treatment. The primary endpoint of this study is the proportion of treatment-naive 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 (500/100 mg and 500/200 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 favourable 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 500/200 mg arm remained non-inferior to the lopinavir/ritonavir arm using the post-hoc analysis dataset.
The closure of this treatment-naive trial does not change the positive benefit-risk profile of Aptivus/ritonavir (500 mg/200 mg) for the highly treatment-experienced patient population for which it is currently indicated.
Boehringer Ingelheim study 1182.33 is a multinational study in 558 treatment-naive 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).
In studies to date, Aptivus® has been well tolerated by most patients and has a safety profile similar to other PIs. The most commonly reported side effects of at least moderate intensity in patients enrolled in the RESIST studies taking Aptivus® are gastrointestinal, including diarrhoea, nausea, vomiting and abdominal pain. Fever, fatigue, headache, bronchitis, depression and rash also occurred.
Aptivus® boosted with low-dose ritonavir has been associated with reports of hepatic adverse events, which have included some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of liver toxicity. The most common moderate to severe laboratory abnormalities were elevated liver enzymes and elevated lipid levels. Most laboratory abnormalities were asymptomatic and most patients were successfully treated without discontinuation.
Aptivus® does not cure HIV infection/AIDS or prevent the transmission of HIV to others. Patients may continue to develop opportunistic infections and other complications associated with HIV disease.
Apart from the EU, Aptivus® has received US marketing authorization by the FDA and was launched there in June 2005. Additional marketing authorizations from different countries have been received or are expected.