《人生终点救助选择研究医学教学[英文版]》由会员分享，可在线阅读，更多相关《人生终点救助选择研究医学教学[英文版]（40页珍藏版）》请在金锄头文库上搜索。
1、Choice of Endpoints for Salvage Studies,Clinical EndpointsAIDS-defining eventsSurvivalQOLMarker-based Endpoints for EfficacyHIV-1 RNACD4,Choice of Endpoints,Choice of Endpoints (Cont.),Endpoints for ToxicityTime to treatment discontinuationTargeted adverse events (e.g. lipodystrophy)Composite Endpoi
2、ntCombine information across different endpoint categories.Time to treatment discontinuation for virological failure or intolerance.,HIV RNA Endpoints,Quantitative (change from baseline to Week x) Time to Virological FailureBinaryCross-sectional; e.g. Above/below threshold at week xFailed by Week x,
3、Cross-Sectional vs. Failure Over Time,Above/Below threshold at week xSnapshot; not affected by transitional changes in HIV levels.Frequent monitoring not required (batch assaying).Missing data at timepoint especially problematic. Failure EndpointsAssessment of response over time; may be affected by
4、transitional changes in HIV levels.Frequent monitoring required (real time assaying).Missing data strategies need to be defined/evaluated.,Time to Failure vs. Cumulative Proportion,Time to FailurePatterns of failure depend on failure time (assumptions). Can be evaluated within an interim analysis (a
5、ccommodates differential follow-up).Cumulative ProportionTime to failure not considered in analysis.Evaluation with interim analysis may be complicated.,If the pooled failure rate is 50%, a time-to-event endpoint has appreciable sample size advantagesExample: 6 months accrual, 1 year additional foll
6、ow-up, 2 arm trial:e.g., 6 months accrual, 1 year additional follow-up, 2 arm trial:50% pooled failure rate, 5% sample size savings70% pooled failure rate, 15% sample size savingse.g., 1 year accrual, 6 months additional follow-up, 2 arm trial:50% pooled failure rate, 12% sample size savings70% pool
7、ed failure rate, 25% sample size savings,Power Advanatges of Time to Event,With moderate study withdrawal, the sample size savings of the time-to-event endpoint increases further.The sample size savings are larger at interim analyses than at final analyses, in proportion to the fraction of subjects
8、who have less follow-up time than the specified interim analysis time.Time-to-event endpoints also have advantages for evaluating covariate effects and for flexibility in extending the study by prolonging the follow-up period.,Analysis Issues,Purely Virologic vs. Composite,Purely VirologicFocuses on
9、 virologic response onlytolerability and safety can be assessed separately Follow-up for viral load is essential after treatment discontinuation.CompositeCombines virologic efficacy, tolerability and safety; overall picture.May differ substantially from purely virologic if toxicity rate is high.Pure
10、ly virologic should be done as secondary endpoint.,Issues in Definition of:,Virologic FailureEarly failure (rise above nadir/baseline, insufficient decline)Amount of time allowed to go below suppression thresholdChoice of threshold for suppression and for loss of suppressionFluctuations due to treat
11、ment holds, intercurrent illness, etc.Regimen CompletionVirologic failure definition (see above)Number of drugs added/changed before declare treatment failureSubjectivity of treatment discontinuation reasons,Clinical Beliefs Underlying the Appropriate Use of Each Endpoint,Purely Virologic Endpoint:T
12、he effect of the investigated therapies on plasma HIV-1 RNA levels captures the essential information needed to define the role of the therapies in clinical practice for the target population.Regimen completion endpoint:The necessity to change regimens more closely measures tangible benefit to a pat
13、ient than does virological failure alone, and, assessing the virologic effect of treatment is unnecessary.,Types of Study Endpoint in HIV Disease Studies,Time to FailureRegimen Completion (384, 372A, A5025)Virologic Failure Week x (388, A5076, A5095)BinaryBelow Threshold at Week x (359, 364, 370, 37
14、3, A5086)Not Fail by Week x: failure is defined as:Rise Above Threshold (A5073)Rise Above Threshold, Early Failure (347, 368, 398, A5080)Rise Above Threshold, Early Failure, Off Treatment (372B, 400, A5064)Cumulative Virologic Failure (343),Composite Endpoints,Combine efficacy and toxicity informati
15、on (e.g. time to Rx discontinuation)Will be more numerous than pure virologic endpoints, but may dilute the effect of treatment. Especially a concern if Rx discontinuation may be unrelated to Rx (pregnancy, imprisonment, moving).,Example,Suppose effect of Rx A (compared to B) reduces percentage reac
16、hing event from 35% to 17.5%. We need 100 patients per arm to have 80% power.Assume Rx discontinuation rate is 10%/yr for both treatments, and is included in endpoint definition.We have more endpoints but only 60% power to detect the treatment difference. We need 50 additional patients per arm for 80% power.,
