Endpoints in HIVAIDS Clinical Trials Qiming Liao, Ph.D. GlaxoSmithKline

1
Endpoints in HIV/AIDS Clinical Trials Qiming
Liao, Ph.D.GlaxoSmithKline
2
Outline

• AIDS epidemic and survival
• HIV/AIDS drugs and treatment
• Surrogate markers and historic change in primary
  endpoint in HIV/AIDS clinical trials
• Reduction in HIV-1 RNA levels
• Time to virologic failure and time to loss of
  virologic response (TLOVR)
• Early virologic non-response
• Issues on choice of endpoints
• Summary

3
(No Transcript)
4
Estimated proportion of persons surviving, by
months after AIDS diagnosis during 19942001 and
by year of diagnosisUnited States
Source CDC
5
Classes of HIV Drugs

• Nucleoside reverse transcriptase inhibitors (ZDV,
  3TC, Combivir, Abacavir, Trizivir, ddI, d4T, TDF,
  ddC)
• Protease inhibitors (APV, IDV, LPV, NFV, RTV,
  SQV, ATV, FPV)
• Non-nucleoside reverse transcriptase inhibitors
  (EFV, DLV, NVP)
• Fusion inhibitors

6
Approved Antiretroviral Agents
3TC/ZDV
TDF
ABC/3TC
FTC/TDF
DLV
ddC
3TC
ABC
EFV
NVP
ddI
ZDV
d4T
FTC
ABC/3TC/ZDV
87
91
92
94
95
96
97
98
99
00
88
89
90
01
04
03
02
93
T-20
NRTI
PI
NNRTI
FI
7
HIV Treatment

• Monotherapy (late 1980s, ZDV)
• Mono and Dual therapy (early 1990s)
• Highly active antiretroviral therapy (HAART,
  since 1996) at least 3 drugs
• Complications of HAART
• viral resistance to drug
• fat redistribution
• hyperlipidemia

8
HIV Care and Clinical Trials

• Standard of care and first line treatment
  regimens (IAS HIV Treatment Guidelines)
• Dynamic therapeutic area (treatment changes over
  time)
• Active control and relatively a large number of
  tries with open label
• Superiority and non-inferiority design
• Naïve population symptom rare

9
Clinical Endpoint and Surrogate Markers

• First ZDV trial death
• Disease progression or death
• Surrogate markers CD4 cell count and HIV-1 RNA
  levels
• Endpoints based on HIV-1 RNA
• reduction from baseline
• proportion of subjects lt 400 (or 50) copies/mL
  (lower limit of the assay)
• time to virologic failure

10
Reduction in HIV-1 RNA

• Surrogate Endpoint Reduction of HIV-1 RNA from
  baseline
• Assay limitation (e.g. HIV-1 RNA lt400 copies/mL,
  or lt50 copies/mL (lower limit), HIV RNA gt750,00
  copies/mL (upper limit))
• Statistical problem What to do with censored
  HIV-1 RNA measurements?

11
Reduction in HIV-1 RNA

• Simplify the problem
• assigning the lower or upper limit (or lower
  limit -1 or upper limit 1) to those censored
  measurements
• analysis of variance (log10 transformation) or
  non-parametric methods
• Take into account of censoring and use
  time-to-event techniques

12
Reduction in HIV-1 RNA

• Assumptions
• no censoring at baseline
• only possible left censoring post baseline
• Reduction of HIV-1 RNA is observed or right
  censored
• Use Kaplan-Meier, logrank test etc.
• Some Issues
• reduction in HIV-1 RNA could be negative (easy to
  deal with shifting)
• reduction depends on Baseline HIV RNA (use Cox
  proportional hazards model)

13
Reduction in HIV-1 RNA

• Other Methods
• Check assumption of normality of HIV-1 RNA
  reductions (in log10 transformation)
• Use parametric analysis analogous to the
  Kaplan-Meier based analysis
• Fit censored analysis of covariance using the
  LIFEREG procedure in SAS
• Accelerated failure time model without worrying
  about the assumption of normality

14
Endpoint of Percent Undetectable on HIV-1 RNA

• Proportion of HIV-1 RNA lt 400 copies/mL (assay
  limit 400) and lt200, 50 copies/mL (assay limit
  50) at Weeks 16, 24, 48
• Rates vary from studies to studies
• Depend on study population, entry criteria
• Analysis methods on handling missing data,
  treatment switch and intensification

15
Endpoint of Percent Undetectable on HIV-1 RNA

• Proportion of HIV-1 RNA lt 50 at Week 24
• ITT MF (missing considered as failure, switch
  included)
• ITT MF, switchF
• Observed (missing ignored, switch included)
• As treated (missing ignored and switch not
  included)
• Model-based approach
• Confusing clinicians and others in the field?
• Cautious on cross study comparisons

16
Time to Virologic Failure

• Virologic failure
• two successive measurements of HIV-1 RNA gt 400
  (50, 200) copies/mL after HIV RNA lt400 (50)
  copies/mL or never get below 400 (50) copies/ml
  by Week 24 (16, 36)
• definition varies
• Two types of virologic failure
• Lack of initial response or non-responder
• Early rebound and later relapse

17
Time to Virologic Failure

• Issues on how to define time to virologic failure
• Non-responder or virologic rebounder, which does
  better?
• Artificial nature of clinical trial (e.g. allow
  24 weeks window for response) creates issues with
  definition of events, censoring, etc -- see
  accompanying examples

18
(No Transcript)
19
(No Transcript)
20
Time to Virologic Failure

• Issues on defining time to virologic failure
• PT 3 PT 4 PT 5
• Method 1 0 0 20
• Method 2 24 24 24
• Method 3 (0,24) (0,24) 20
• (0,24) means censored between 0 and 24
• Which method is more reasonable?
• Method 3 with some statistical challenge due to
  both right and left censoring

21
More Time to Event Endpoints

• Time-to-event endpoints
• time to virologic failure (TVF)
• time to virologic response (TVR)
• duration of viral suppression (DVS)
• TVFTVR DVS
• composite endpoint
• Time to loss of virologic response (TLOVR)
  (regimen termination end point (RT))

22
Composite Endpoint

• Time to loss of virologic response (regimen
  termination), defined as the first occurrence of
• virologic failure
• lack of initial response, early rebound, or later
  relapse
• permanent treatment discontinuation
• AIDS-defining illness
• death
• study withdrawal

23
Time to Virologic Failure VS TLOVR

• Time to virologic failure versus time to regimen
  termination endpoint (TLOVR)?
• NIH/FDA Workshop on HIV Endpoints (February,
  2001)
• Gilbert, DeGruttola et al. Virologic and regimen
  termination surrogate end points in AIDS clinical
  trials, JAMA 2001
• How to monitor the study? If co-primary endpoints
  are chosen, how to define stopping rules?

24
Time to Virologic Failure VS TLOVR

• Both endpoints are imperfect surrogates for
  clinical endpoints
• large uncertainties regarding how well treatment
  effects on the surrogate endpoints predict
  treatment effects on clinical outcomes
• e.g., a meta-analysis of 16 clinical trials of
  dual nucleoside regimens showed limited surrogacy
  of the viral load change endpoint
• virologic information does not necessarily
  measure problems associated with treatment
• e.g., toxic effects, adherence difficulties,
  resistance

25
Relative Advantages of a TLOVR Endpoint

• In studies of sequences of regimens, it more
  directly counts the costs of expending regimens
• toxicity costs
• non-adherence costs
• drug resistance costs
• Higher event rate compared to a purely virologic
  endpoint
• disseminate study results more quickly
• caution more events dont necessarily result
  more statistical power

26
Relative Advantages of a TLOVR Endpoint

• HIV-1 RNA alone (purely virologic endpoint) can
  be misleading when patients with tolerability
  problems on an inferior regimen are salvaged with
  a superior regimen
• TLOVR reflects the current belief that the longer
  the first regimen effectively suppresses HIV RNA
  with tolerable side effects the more patients
  will benefit Blinding may be compromised during
  the first treatment regimen termination for side
  effects
• Patient management is no longer uniform after the
  first treatment regimen termination
• Rebound may occur during regimen modification
• leading to a HIV-1 RNA endpoint that is not
  related to the virological efficacy of the
  regimen under study

27
Relative Advantages of a Purely Virologic Failure
Endpoint

• Allows separate investigation of efficacy and
  safety
• Defined more objectively than a regimen
  termination endpoint
• less dependent on physician/patient choice
• less subject to bias in open-label studies
• Its use as a primary endpoint assures that a
  secondary analysis of a regimen termination
  endpoint can be carried out

28
Relative Advantages of a Purely Virologic Failure
Endpoint

• Gives equal weight to
• mild treatment-limiting side effects and serious
  irreversible toxicities
• virologic endpoints regardless of the remaining
  therapeutic options
• treatment-related failures and loss-to-follow-up
• Encourages less diligent follow-up after initial
  regimen termination
• Leads to limited ability to assess the extent of
  remaining therapeutic options

29
Clinical Beliefs Underlying the 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
• TLOVR endpoint
• expending a regimen more closely measures
  tangible harm

30
Recommendations from FDA GuidanceClinical
Considerations for Accelerated and Traditional
Approval of ART Drugs Using Plasma HIV RNA
Measurements

• Blinded comparisons with well-characterized
  controls are preferable
• Studies that clearly show the investigational
  drugs contribution to decreases in HIV RNA as
  part of a combination regimen (Accelerated
  Approval 24 weeks)
• Studies that show the drugs contribution toward
  sustained suppression of HIV RNA (Traditional
  Approval 48 weeks)
• Critical that management decisions be made in
  uniform manner
• TLOVR endpoint analysis is required
• Sensitivity analyses are encouraged
• Pure Virological ITT as well as any other
  analysis thought useful by sponsor may also be
  performed

31
Abacavir/Combivir versus Indinavir/Combivir in
Therapy Naïve Adults at 48 Weeks (CNAAB3005)

• Multi-center, double-blind, controlled study in
  which 562 HIV-infected, therapy-naive adults with
  a pre-entry plasma HIV RNA gt10,000 copies/mL were
  randomized to receive either
• ZIAGEN (300 mg twice daily) plus COMBIVIR
  (lamivudine 150 mg/zidovudine 300 mg twice
  daily), or
• Indinavir (800 mg 3 times a day) plus COMBIVIR
  twice daily.
• Study participants were male (87), Caucasian
  (73), African-American (15), and Hispanic (9)
• Median age was 36 years, the median pretreatment
  CD4 cell count was 360 cells/mm3, and median
  plasma HIV RNA was 4.8 log10 copies/mL

32
CNAAB3005Virologic Endpoint and Options

• Virologic endpoint confirmed HIV RNA gt 400
  copies/mL at Week 16 or later
• Patients who met virologic endpoint had 3 options
• Continue randomized therapy
• Discontinue randomized therapy and receive
  open-label ABC (300mg BID) and/or IDV (800mg q8h)
  and/or 3TC/ZDV (150/300mg BID) and/or add any
  licensed ART
• Discontinue all study medication and withdraw
  from study
• Patients who permanently discontinued study med
  prior to Week 16 were to be followed by
  investigator

33
CNAAB3005Subject Accountability at Week 48
IDV/COM
ABC/COM
34
(No Transcript)
35
(No Transcript)
36
ACTG 364 Study Design Phase II, Randomized,
Partially Double - Blind
ACTG 364
ACTG 302
R A N D O M I Z E
NFV EFV placebo NRTIs
ACTG 175
NFV placebo EFV NRTIs
NFV EFV NRTIs
ACTG 303
1 or 2 new NRTIs assigned as part of dual NRTI
components (d4T ddI, d4T3TC, or ddI3TC)
Source Presentation by Bosch and Gilbert on HIV
Endpoint Workshop, 2001
37
ACTG 364
38
ACTG 364
39
Issues on Salvage Therapy for Experienced Patients

• Differences relative to naïve setting
• More heterogeneity of drug histories and
  treatments
• More advance disease stage
• Patients may be more willing to tolerate
  mild/moderate events to derive therapeutic
  benefit
• Patients may have fewer future treatment options
• Primary endpoint and definition of VF may be
  different
• CD4 cell count may be more predictive of
  clinical benefit

40
Endpoint on Salvage Therapy for Experienced
Patients

• Endpoints of proportion of HIV-1 RNA lt50 (400)
  copies/mL or virologic failure may not be the
  best in populations where a moderate suppression
  in plasma HIV-1 RNA may confer clinical benefit
• Change from baseline may be more appropriate
• Appropriate data handling and average methods
  (e.g., LOCF, AAUCMB etc.) are required in these
  settings to minimize bias

41
Endpoint on Early Virologic Non-Response

• Time to Virologic failure and TLOVR endpoints not
  valid
• Not enough time to allow patients to have viral
  decline below assay limit (lt400, 50 copies/mL)
• Patients with different follow-up time
• Unexpected early clinical concern over randomized
  treatment regimen (e.g. ESS30009)

42
ESS30009 Study Design Open-label, randomized,
multicenter trial

• Entry criteria
• ? 18 years old
• ART-naïve (?14 days ART)
• VL ? 5,000 copies/mL
• No CD4 restrictions

48 weeks
EFV 600mg QD ABC/3TC FDC QD n180 planned
Screening
Randomize
TDF 300mg QD ABC/3TC FDC QD n180 planned

• Primary endpoint
• Proportion with HIV-1 RNA lt50 c/mL at week 48

Randomization (11) stratified by HIV-1 RNA
lt100K or ?100K c/mL
43
Unplanned Interim Analysis

• Following rapid study accrual, several cases of
  early virologic non-response in the TDF ABC/3TC
  arm were reported
• Urgent unplanned interim analysis performed for
  subjects with ?8 weeks HIV-1 RNA data (N194 of
  345 randomized patients)
• Virologic non-response defined as
• 1) lt2.0 log decline in HIV-1 RNA by week 8 or
• 2) ?1.0 log rebound from nadir at any subsequent
  visit or
• 3) Confirmed HIV-1 RNA gt400 c/mL following two
  consecutive HIV-1 RNA lt50 c/mL

44
Baseline Characteristics For subjects with at
least 8 weeks HIV-1 RNA data

• EFV ABC/3TC TDF ABC/3TC (N92) (N102)
  
• Median age, years 36.0 38.5
• Male Sex 90 92
• Race Black / Hispanic / White 37 / 9 / 53
  29 / 9 / 62CDC Class C 9 lt1
• Median HIV-1 RNA, log10 c/mL 4.71 4.53
  Median CD4 count, cells/mm3 280.5 251.5
  

45
EFV ABC/3TC HIV-1 RNA Response For subjects
with at least 8 weeks HIV-1 RNA data (N92)
HIV-1 RNA c/mL
46
TDF ABC/3TC HIV-1 RNA Response For subjects
with at least 8 weeks HIV-1 RNA data (N102)
HIV-1 RNA c/mL
47
Virologic Non-Response For subjects with at
least 8 weeks HIV-1 RNA data

• Criteria EFV ABC/3TC TDF ABC/3TC
  (N92) (N102)
• 1 lt2.0 log decline from 3/92 (3.3) 32/102
  (31.4) baseline by week 8
• 2 ?1.0 log rebound 0/92 (0) 8/102
  (7.8) from nadir
• Both criteria 1 and 2 met 2/92
  (2.2) 10/102 (9.8)
• Total 5/92 (5.4) 50/102 (49)

No subjects met virologic non-response criteria
3Difference between arms plt0.001, 95 CI
-54.3, -32.8
48
ESS30009 Discussion

• TDF ABC/3TC resulted in an unexpectedly high
  rate of early virologic non-response
• A large proportion of patients with non-response
  to TDF ABC/3TC had K65R and M184V
• At early follow-up, EFV ABC/3TC resulted in a
  rapid decline in viral load, consistent with
  previous trials

49
Structured Treatment Interruption (STI)

• STI strategies (e.g. one week on, one week off 2
  months on, 1 months off CD4 count guided (lt350
  on, gt350 off), etc. )
• Long term studies to evaluate
• Endpoint (taking into resistance cost, drug cost,
  etc.)

50
Choice of Endpoints

• Which endpoint to choose as the primary endpoint?
• all endpoints are not created equal
• vary with patient population (naïve or
  experienced) and study objectives
• driven by the medical/scientific questions of
  interest
• power and accommodation of missing data
• which is best surrogate for a long-term outcome?

51
Choice of Endpoints

• How to incorporate dropout/missing data into
  analysis
• treat dropouts as censored observations
• treat dropouts as failures
• model dropout process
• Which to choose as primary analysis method for
  primary endpoint?
• Check sensitivity of analysis results

52
Summary

• Study endpoints using surrogate markers
• Time-to-event techniques to analyze censored
  measurement data
• Statistical methods on time to failure data with
  fixed allowable time for response
• Issues on choosing primary endpoint for HIV
  clinical trials (pure time to virologic failure
  or composite endpoint)
• Endpoint on detecting early virologic
  non-response
• Endpoint on strategic trials