# Presentation: 424081

## Choice of Endpoints for Salvage Studies

## Clinical Endpoints

AIDS-defining events
Survival
QOL

Marker-based Endpoints for Efficacy

HIV-1 RNA
CD4

**AIDS-defining events**
**Survival**
**QOL**
_**Marker-based Endpoints for Efficacy**_
**HIV-1 RNA**
**CD4**

**Choice of Endpoints**

## Choice of Endpoints (Cont.)

_**Endpoints for Toxicity**_
**Time to treatment discontinuation**
**Targeted adverse events  (e.g. lipodystrophy)**
_**Composite Endpoint**_
**Combine 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 Failure**
**Binary**
**Cross-sectional; e.g. Above/below threshold at                                                                                                                                                                                                                 week x**
**Failed by Week x**

## Cross-Sectional vs. Failure Over Time

_** **__**Above/Below threshold at week **__***x***_
**Snapshot; not affected by transitional changes in HIV levels.**
**Frequent monitoring not required (batch assaying).**
**Missing data at timepoint especially problematic.**
** **_**Failure Endpoints**_
**Assessment of response over time; may be affected by 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 Failure**_
**Patterns of failure depend on failure time (assumptions).**
** ****Can be evaluated within an interim analysis (accommodates differential follow-up).**
_**Cumulative Proportion**_
**Time 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 advantages
Example:  6 months accrual, 1 year additional follow-up, 2 arm trial:

e.g., 6 months accrual, 1 year additional follow-up, 2 arm trial:
50% pooled failure rate, 5% sample size savings
70% pooled failure rate, 15% sample size savings

e.g., 1 year accrual, 6 months additional follow-up, 2 arm trial:
50% pooled failure rate, 12% sample size savings
70% pooled failure rate, 25% sample size savings 

**Example:  6 months accrual, 1 year additional follow-up, 2 arm trial:**
**e.g., 6 months accrual, 1 year additional follow-up, 2 arm trial:**
**50% pooled failure rate, 5% sample size savings**
**70% pooled failure rate, 15% sample size savings**
**e.g., 1 year accrual, 6 months additional follow-up, 2 arm trial:**
**50% pooled failure rate, 12% sample size savings**
**70% pooled 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 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.

**The sample size savings are larger at interim analyses than at final analyses, in proportion to the fraction of subjects 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 Virologic**_
**Focuses on virologic response only**
**tolerability and safety can be assessed separately**
** ****Follow-up for viral load is essential after treatment discontinuation.**
_**Composite**_
**Combines virologic efficacy, tolerability and safety; overall picture.**
**May differ substantially from purely virologic if toxicity rate is high.**
**Purely virologic should be done as secondary endpoint.**

## Issues in Definition of:

_**Virologic Failure**_
**Early failure (rise above nadir/baseline, insufficient decline)**
**Amount of time allowed to go below suppression threshold**
**Choice of threshold for suppression and for loss of suppression**
**Fluctuations due to treatment holds, intercurrent illness, etc.**
_**Regimen Completion**_
**Virologic failure definition (see above)**
**Number of drugs added/changed before declare treatment failure**
**Subjectivity of treatment discontinuation reasons**

## Clinical Beliefs Underlying the Appropriate Use of Each Endpoint

**Purely Virologic Endpoint:**
**The 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 patient than does virological failure alone, and, assessing the virologic effect of treatment is unnecessary.**

## Types of Study Endpoint in HIV Disease Studies

_**Time to Failure**_
**Regimen Completion (384, 372A, A5025)**
**Virologic Failure ******** Week x (388, A5076, A5095)**
_**Binary**_
**Below Threshold at Week x (359, 364, 370, 373, 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 information (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 reaching 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.**

## Example Continued

**“****Pure” Failure**
**100 Evaluable Patients**

**Failure including Rx Discontinuation**
**100 Evaluable Patients**

## ACTG 359:Proportion vs. Change 

**ACTG 359 is a randomized, partially double-blinded, multicenter factorial study of six oral combination antiretroviral regimens:**
**	****	****	****DLV****	****-****	****RD**
**	****	****RTV****	****ADV****	****-****	****RA**
**	****	****	****DLV + ADV****	****-****	****RDA**
**SQV**
**	****	****	****DLV****	****-****	****ND**
**	****	****NFV****	****ADV****	****-****	****NA**
**	****	****	****DLV + ADV****	****-****	****NDA**
**Subjects received randomized study treatment for 24 weeks**

## ACTG 359: Proportion Below Detection

**ACTG 359: Proportion Below Detection**

## ACTG 359: Proportion Below Detection

**ACTG 359: Proportion Below Detection**

## ACTG 359: Proportion Below Detection

**ACTG 359: Proportion Below Detection**

## ACTG 359: Mean HIV-1 RNA Change from Baseline

**ACTG 359: Mean HIV-1 RNA Change from Baseline**

## Data Completeness

**Data Descriptions**
**Above 90% of subjects had week 16 virologic and immunologic data.**
**# of subjects with missing RNA data at week 16.**
**  ****Treatment****	****	****RD****	****RA****	****RDA****	****ND****	****NA****	****NDA**
**	****   ****n****	****	****	****5****	****3****	****6****	****5****	****1****	****3**
** **
**Data were assumed to be missing at random.**

## Primary Efficacy Comparison

**Proportions of HIV-RNA below 500 at week 16**
**	****	****	****RTV****	****	****NFV**
**	****	****28% (35/125)****	****33% (42/127)**
**                            ****P = 0.513, Fisher’s exact test**
**	****       ****DLV****	****          ADV****	****  DLV + ADV **
**      ****40% (34/85)****	****      18% (16/88)****	****  33% (17/79)**
**                           ****P = 0.006, Chi-square test**

## Secondary Efficacy Analysis: RNA Change

**HIV RNA week 16 median change from baseline**
** ****Treatment****	****	****   RD****	****   RA****	****   RDA   ND****	****   NA****	****   NDA**
**   ****in log10****	****	****-0.41****	****-0.16****	****-0.21****	****-0.61****	****-0.08****	****-0.05**
**RTV vs. NFV: p = 0.834 (Logrank), p = 0.586 **
**	****(Prentice-Wilcoxon)**
**DLV vs. ADV: p = 0.003, p = 0.011;**
**	****DLV vs. DLV + ADV: p = 0.262, p = 0.231;**
**	****ADV vs. DLV + ADV: p = 0.104, p = 0.258.**

## ACTG 364

**ACTG 364**

## ACTG 364

**ACTG 364**

## ACTG 364

**ACTG 364**

## Loss to Follow-Up

**Need a policy for handling loss to follow-up**
**Drop-out as censored/failure may be biased**
**Sensitivity analyses with various levels of association between drop-out and failure events**

## Slide 28

## Slide 29

## Slide 30

## ACTG 398

**Subjects were stratified for prior PI (protease inhibitor) exposure, by selective randomization to one of four treatment arms:**
**SQV Arm: Amprenavir (APV) + Saquinavir (SQVsgc) + Abacavir (ABC) + Efavirenz (EFV) + Adefovir (ADV)**
**IDV Arm: APV + Indinavir (IDV) + ABC + EFV + ADV**
**NFV Arm: APV + Nelnavir (NFV) + ABC + EFV + ADV**
**Placebo Arm: APV + Placebo (matched to SQVsgc, IDV or NFV)+ ABC + EFV + ADV**

## ACTG 398 Continued

**Design and Ideal Enrollment**
**	****	****	****	****	****Arms**
**Prior PI Exposure****	****	****SQV****	****IDV****	****NFV****	****Placebo****	****Total**
**SQV only ****	****	****X ****	****25 ****	****25 ****	****15 ****	****65**
**IDV/RTV only ****	****	****25 ****	****X ****	****25 ****	****15 ****	****65**
**NFV only ****	****	****25 ****	****25 ****	****X ****	****15****	****65**
**NFV and IDV/RTV ****	****	****33 ****	****X ****	****X ****	****22 ****	****55**
**NFV and SQV ****	****	****X ****	****33****	****X ****	****22 ****	****55**
**SQV and IDV/RTV ****	****	****X ****	****X ****	****33****	****22 ****	****55**
**NFV, SQV and IDV/RTV ****	****17 ****	****17 ****	****17 ****	****17 ****	****68**
**	****	****Total ****	****100 ****	****100 ****	****100 ****	****128 ****	****428**

## ACTG 398

**ACTG 398**

## ACTG 398 Continued

**Estimated Virologic Failure at Week 24 for MAR and M=F**
** ****(Kaplan-Meier)**
**Treatment ****	****NNRTI ****	****M=F ****	****MAR**
**Arm ****	****Experienced? ****	****Failure (95%CI) ****	****Failure (95%CI)**
**SQV ****	****Yes ****	****0.85 (0.74, 0.95) ****	****0.76 (0.62, 0.90)**
**	****No ****	****0.54 (0.43, 0.66) ****	****0.41 (0.29, 0.53)**
**IDV ****	****Yes ****	****0.87 (0.75, 0.99) ****	****0.80 (0.66, 0.94)**
**	****No ****	****0.53 (0.37, 0.69) ****	****0.42 (0.26, 0.59)**
**NFV ****	****Yes ****	****0.73 (0.62, 0.83) ****	****0.66 (0.54, 0.77)**
**	****No ****	****0.55 (0.43, 0.67) ****	****0.48 (0.36, 0.60)**
**Placebo ****	****Yes ****	****0.91 (0.83, 0.98) ****	****0.82 (0.73, 0.92)**
**	****No ****	****0.63 (0.54, 0.73) ****	****0.52 (0.42, 0.63)**

## ACTG 398 Continued

**Primary Comparison of Treatment Arms vs. Placebo**
**P-values for RNA < 200 copies/ml at Week 24**
**SQV vs Placebo ****	****IDV vs Placebo ****	****NFV vs Placebo ****	****SQV/IDV/NFV vs Placebo**
**	****0.25 ****	****0.29 ****	****0.004 ****	****0.002**
**Results based on the exact test with stratification by prior PI and NNRTI experience.**

## ACTG 398 Continued

**P-values for Confirmed Virologic Failure at/before Week 24**
**	****	****SQV vs Placebo ****	****IDV vs Placebo ****	****NFV vs Placebo ****	****SQV/IDV/NFV vs Placebo**
**M=F ****	****	****0.62 ****	****1.00 ****	****0.005****	****0.026**
**MAR ****	****	****0.74 ****	****0.83 ****	****0.005****	****0.038**
**Notes: Results based on the exact test with stratification by prior PI and NNRTI experience.**
**MAR = Missing-at-random (missing RNA samples ignored)**
**P-values for Time to Confirmed Virologic Failure**
**	****	****SQV vs Placebo ****	****IDV vs Placebo ****	****NFV vs Placebo ****	****SQV/IDV/NFV vs Placebo**
**M=F ****	****	****0.78 ****	****0.83 ****	****0.006****	****0.040**
**MAR ****	****	****0.98 ****	****0.70 ****	****0.003****	****0.038**
**Notes: Results based on the stratified log-rank test with stratification by prior PI and NNRTI**
**experience.**
**MAR = Missing-at-random (missing RNA samples ignored)**

## Analysis of Quantitative Endpoints

**Censored data methods required (log-rank, Prentice log-rank**
**Bias results from excluding missing data**
**Lost observations carried forward can be very biased**
**Consider last rank carried forward for rank-based analysis**

## Count study withdrawal as failure or as censored?

each analysis is likely biased

recommend carrying out both analyses as well as more sophisticated sensitivity analyses

**each analysis is likely biased**
**recommend carrying out both analyses as well as more sophisticated sensitivity analyses**

**Discussion Points**

## What are the criteria for selecting a primary endpoint? 

Optimally addresses the primary objective, taking into account the patient population and the study drugs

Within the pool of possible surrogate markers, it is maximally accurate as a replacement for true clinical endpoints

**Optimally addresses the primary objective, taking into account the patient population and the study drugs**
**Within the pool of possible surrogate markers, it is maximally accurate as a replacement for true clinical endpoints**

**Discussion Points**

## If the primary endpoint is binary, the Chi-squared test and Fisher’s exact test for a treatment difference are biased if there are censored data
A Z-test based on the difference in   Kaplan-Meier estimates of the proportion failed is unbiased and efficient 

use this test routinely

**A Z-test based on the difference in   Kaplan-Meier estimates of the proportion failed is unbiased and efficient **
**use this test routinely**

**Analysis Points**