Considerations for the choice and interpretation of endpoints in international trials of antiretroviral therapies Victor De Gruttola. Big Issues. When do results from a study in one region apply to another region?
When do results from a study in one region apply to another region?
Do safety and efficacy endpoints have the same meaning across populations of interest?
Can we improve ability to generalize results by investigating predictors of and surrogates for efficacy and safety endpoints in the populations of interest?
Are populations similar with regard to:
- predictors of safety and efficacy and safety in presence and absence of treatment (Rx)?
- surrogates for Rx effects
Of special interest, factors that modify the effect of Rx on endpoints.
Botswana endpoints in
BOTSWANA: World AIDS Day March
What is the best first line therapy and adherence strategy for reducing virological failure with development of resistance.
Factorial Design: 660 patients
Factor 1: Efavirenz vs Nevirapine
Factor 2: ZDV/3TC vs D4T/3TC vs ZDV/ddI
Factor 3: Treatment Partner (Mopati) vs SOC
Time to virological failure with significant resistance mutations as defined by the Stanford website. Last on-treatment viral load will be genotyped
Arm A: (BID) ZDV/3TC + efavirenz (EFV) or nevirapine (NVP)
Arm B: (QD)+atazanavir (ATV) + FTC +d4T-XR
Arm C: (QD) FTC + tenofovir (TDF) + EFV or NVP
- Disease progression. New or recurrent AIDS defining opportunistic infection or malignancy after 12 weeks of therapy.
- Virologic failure. Plasma HIV-1 RNA > 1,000 copies/mL on two consecutive measurements after 24 weeks of therapy.
Power: 1250 patients (allowing 10% dropout rate) provides 80% power to reject a hazard ratio of > 1.4 if treatments being compared have same true endpoint rates. Arms B and C compared to arm A.
UNAIDS 2001 endpoints in
A5175 Site Locations
For study 1:
For study 2:
For study m:
- is surrogate for T across regions
- responds similarly to X (and is
similar in untreated pts.) across
International research on ART exemplifies problems that arise in generalizing across populations. Specifically, we are concerned about variability in: