# Presentation: 859890

## Overview of Large Prospective Trials of Thiazolidinediones

**Karen Murry Mahoney, MD, FACE**
**Medical Officer**
**Division of Metabolism and Endocrinology Products**

## Content of Presentation

**Overview of studies’ characteristics**
**Overview of myocardial ischemia safety data for ADOPT, DREAM and RECORD (RSG); and PROactive (PIO)**
**ADOPT and PROactive study reports have been submitted to FDA; therefore more detail**
**Analyses of similar CV endpoints across data sources**
**Summary**

## Transition from Meta-Analysis to Consideration of Large Prospective Randomized Trials

**FDA meta-analysis has signal of increased myocardial ischemic risk for RSG**
**Common after meta-analyses to look at other data sources for consistency in signal**
**Large, prospective, randomized, controlled trials do not have some of the problems of meta-analyses**
**For any drug, all data sources have limitations**

## Tables of Data Source Characteristics

|  | ADOPT
(RSG) | DREAM
(RSG) | RECORD
(RSG) | PROactive
(PIO) | FDA Meta-Analysis
(RSG) |
| --- | --- | --- | --- | --- | --- |
| Status | Study complete, full report under review | Study complete, no study report to FDA yet | Ongoing | Study complete, review complete | Studies complete, review complete |
| Question | Durability as monotherapy | Progression from IGT to DM | CV outcome | CV outcome | Glycemic control |
| # Patients | 4351 | 5269 | 4447 | 5238 | 14,237 |
| Duration | 4-6 yrs
 | Median 3 yrs | Median 6 yrs planned | Mean 34.5 mo
 | 38/42 <=6 mo; mean appr 6 mo |
| TZD Pt-Yr Exposure | 4954 pt-yrs | 8014 pt-yrs | 8369 pt-yrs to date | 6482 pt-yrs | 4146 pt-yrs |

## Tables of Data Source Characteristics (cont)

|  | ADOPT
(RSG) | DREAM
(RSG) | RECORD
(RSG) | PROactive
(PIO) | FDA Meta-Analysis (RSG) |
| --- | --- | --- | --- | --- | --- |
| Pt Pop | DM2 <= 3 y | IGT or IFG | DM2, inad control on MET or SU | DM2 with hx macrovasc dz | DM2, varied pops |
| Study Drug | RSG | RSG or RSG+RAM | Add-on RSG | Add-on PIO | RSG (mono, coadmin, or add-on) |
| Control | SU or MET | RAM or PBO
(2x2 factorial) | Add-on MET or SU | Add-on PBO | Varied |
| I° Endpt | Monotherapy failure | DM2 or death | Death or CV hosp  | Composite of 7 macrovasc events | Myocard isch events, broad composite |
| Isch Event Adjudic? | No | Yes | Yes | Yes | Post hoc for GSK meta-analysis |

## ADOPTA Diabetes Outcome Progression Trial

## ADOPT Design and Disposition:  Key Points

**Objectives:  examine time to monotherapy failure, and examine general safety (not a specific CV outcome study)**
**High withdrawal rate (monotherapy failure and other reasons)**
**Differential exposure (pt-yrs):       RSG 4954, MET 4906, ****SU 4244**

## Withdrawal Rates in ADOPT:Proportion of Patients on Study by Treatment Group

## Preliminary Review of Cardiovascular Safety Results:  Death

|  | RSG
N=1456, PY=4954
n (%) 
[rate/100 PY] | SU
N=1441, PY=4244
n (%) 
[rate/100 PY] | MET
N=1454, PY=4906
n (%) 
[rate/100 PY] |
| --- | --- | --- | --- |
| All deaths up to 30 days p Tx 
(end of routine AE collection) | 
12 (0.8%) 
[0.2/100 PY] | 
21 (1.5%) 
[0.5/100 PY] | 
15 (1.0%) 
[0.3/100 PY] |
| All reported deaths 
(not routinely collected >30 d p Tx) | 
34 (2.3%) 
[0.7/100 PY] | 
31 (2.2%) 
[0.7/100 PY] | 
31 (2.1%) 
[0.6/100 PY] |

## ADOPT Serious CV Adverse Events (Rates/100 PY)

**Cardiac MedDRA® System Organ Class Events:               RSG 1.6, SU 1.2, MET 1.7**
**Individual CV SAE terms:  ****	****	****	****                             -1/104 observed SAE terms had rate/100 PY >=0.1 higher for ****	****RSG than for SU and MET.                                                         -0/104 terms had rate/100 PY >=0.2 higher for RSG than for ****	****MET and SU.                                                                                 ****-“Myocardial infarction” term (not all terms for MI).                  ****	****RSG 0.4, SU 0.2, MET 0.3**
**Myocardial ischemia event grouping by GSK:                         -****No significant difference between groups for overall    ****	****myocardial ischemic events or components****.****                                               -MI SAEs RSG 0.5, SU 0.3, MET 0.4.  Not stat sig.**
**FDA cardiologist event groupings (>49,000 records, >40 endpoints):  No significant imbalances; overall rate of MI seemed low in proportion to rate of strokes.**

## ADOPT KM Curves:  Time to Myocardial Ischemic Event

## Limitations of ADOPT

**Was an efficacy and general safety trial, and not a CV endpoint trial; no predefined CV event adjudication**
**High withdrawal rate**
**Differential pt-yr exposure (lower for SU)**
**Active comparator may obscure absolute risk**
**Adverse event ascertainment only out to 30 days after cessation of study drug**
**Early diabetic population may not be generalizable**
**Small numbers of cardiovascular events increase uncertainty of estimates**

## Strengths of ADOPT

**Duration much longer than mean duration of studies in meta-analysis**
**Large number of patients**
**Treatment groups well-matched at baseline; less heterogeneity than in meta-analysis**
**Randomization maintained for adverse event analyses**
**Review revealed few problems in ascertainment and coding**
**Active comparator design consistent with “real-world” treatment decisions**

## Summary of Preliminary CV Safety Findings from ADOPT

**Has not detected a significant difference in myocardial ischemic event rates between RSG and MET or SU**
**Cannot rule out a difference in myocardial ischemic risk**
**Higher rate of heart failure events with RSG than with SU**
**Study has limitations, including high withdrawal rate**

## Possible Contributions of ADOPT to Evaluation of Myocardial Ischemic Risk for Rosiglitazone

**More patient-year exposure for this single trial than for all trials in meta-analysis combined**
**Provides information in a population with relatively early diabetes**
**Provides information regarding risk relative to the two most commonly prescribed diabetes drug classes**

## DREAMDiabetes Reduction Assessment with Ramipril and Rosiglitazone

## DREAM Status, Design and CV Events

**Prospective, R, DB, PC**
**2x2 factorial design; both RSG and ramipril studied**
**Examined progression from impaired glucose tolerance to overt DM**
**2635 pts RSG; 2634 pts non-RSG**
**Total mortality equal for RSG and non-RSG**
**Numerically more CV composite (macrovasc + HF) events for RSG than for non-RSG**
**Significantly more HF events for RSG than for non-RSG**

## DREAM Angiotensin Converting Enzyme (ACE) Inhibitor Interaction

## Possible Contributions of DREAM to Evaluation of Myocardial Ischemic Risk for Rosiglitazone

**Almost double the patient-year exposure for this single trial than for all trials in meta-analysis combined**
**Provides information in a “prediabetic” population**
**Provides information regarding risk relative to placebo**
**Raises the question of the contribution of an interaction between RSG and ACEI for CV risk**

## RECORDRosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes

## Status and Design

**Ongoing; mean follow-up 3.75 yrs; interim analysis published**
**Prospective, R, open-label, CV outcome study**
**Pt pop = DM2 with inadequate control on MET or SU**
**BL MET pts randomized to add-on RSG (1117 pts) or add-on SU (1105 pts)**
**BL SU pts randomized to add-on RSG (1103 pts) or add-on MET (1122 pts)**
**Primary endpoint = death or cardiovascular hospitalization**
**Lower-than-expected event rate has affected planned statistical power**

## Interim Cardiovascular Safety Data from RECORD (Adjudicated Events)

| Endpt | RSG
n (%) | Contr
n (%) | HR 
(95% CI) | p-value |
| --- | --- | --- | --- | --- |
| I° (Death or CV Hosp), incl HF | 
217 (9.8) | 
202 (9.1) | 
1.08 (0.89, 1.31) | 
0.43 |
| I° (Death or CV Hosp), 
w/o HF | 
195 (8.8) | 
194 (8.7) | 
1.01 (0.83, 1.23) | 
np |
| All-cause Mort | 74 (3.3) | 80 (3.6) | 0.93 (0.67, 1.27) | 0.63 |
| CV Mort | 29 (1.3) | 35 (1.6) | 0.83 (0.51, 1.36) | 0.46 |
| Acute MI | 43 (1.9) | 37 (1.7) | 1.16 (0.75, 1.81) | 0.50 |

## Conditional Power Calculations for RECORD

**When evaluating interim trial data, conditional power is the probability that the trial will demonstrate statistical significance for an endpoint at the end of the trial *****conditional***** on the data observed in the trial thus far.**
**Calculations dependent on what one has *****already***** seen in the trial (e.g. HR, SE, information fraction)**
**Calculations also dependent on what one *****expects***** regarding the rest of the data to come (e.g. what the future HR might be) **

## RECORD Conditional Power Calculations

## Possible Contributions of RECORD to Evaluation of Myocardial Ischemic Risk for Rosiglitazone

**Is a cardiovascular outcome study**
**To date, over twice the patient-year exposure for this single trial than for all trials in meta-analysis combined**
**Already has more composite events across treatment groups than all trials in meta-analysis combined**
**Provides information in a diabetic population failing monotherapy**
**Provides information regarding risk with add-on RSG vs add-on MET or SU**
**Has high conditional power to exclude a hazard ratio of 1.4 (similar to the point estimate in the meta-analysis), or 1.3, but lower power to exclude a hazard ratio of 1.2**

## PROactiveProspective Pioglitazone Clinical Trial in Macrovascular Events

## PROactive Design: Key Points

**CV outcome study**
**Add-on PIO = 2605 pts                           Add-on PBO = 2633 pts**
**All had history of macrovascular disease**
**Excluded HF NYHA FC II or higher**
**Excluded pts on insulin monotherapy**
**Other meds, including other DM meds, were to be titrated or added to achieve IDF goals for DM, Htn and lipids; however, differences at endpoint favored PIO.**

## Primary Efficacy Endpoint

**A composite of:**
**All-cause mortality**
**Nonfatal myocardial infarction (including silent MI)**
**Stroke**
**Acute coronary syndrome**
**Cardiac intervention (CABG or PCI)**
**Major leg amputation (above ankle)**
**Bypass surgery or revascularization in the leg**
**No endpoints included heart failure.**

## PROactive Results

| Endpoint | Add-On PIO
N=2605
n (%) | Add-on PBO
N=2605
n (%) | HR 
(95% CI), 
p-value |
| --- | --- | --- | --- |
| Primary composite | 
514 (19.7%) | 
572 (21.7%) | 0.90 
(0.80, 1.02), p=0.0954 |
| CV mort (predefined II°) | 
127 (4.9%) | 
136 (5.2%) | 0.94 
(0.74, 1.20), p=0.6163 |
| All-cause mort + MI + stroke (II°) | 
301 (11.6%) | 
358 (13.6%) | 0.84 
(0.72, 0.98), p=0.0277 |

## PROactive Subgroups by Baseline Oral Diabetes Therapy (for Endpoint of All-cause Mortality, Stroke and MI [Excluding Silent MI])

| Baseline OHA | Add-on PIO
n/N (%) | Add-on PBO
n/N (%) | HR (95% CI) |
| --- | --- | --- | --- |
| Neither MET nor SU | 29/212 
(13.7%) | 23/214 
(10.7%) | 1.29 
(0.75, 2.23) |
| MET only | 76/769 
(9.9%) | 107/793 (13.5%) | 0.72 
(0.54, 0.97) |
| SU only | 104/800 (13.0%) | 116/791 (14.7%) | 0.89 
(0.68, 1.15) |
| MET + SU | 92/824 
(11.2%) | 112/835 (13.4%) | 0.82 
(0.62, 1.08) |

## PROactive Addendum with Pooled Studies

**Submitted analysis of their later secondary endpoint (all-cause mort + MI + stroke) across pooled clinical trials database**
**Overall HR 0.78 (95% CI 0.58, 1.06), p=0.12**
**Datasets not submitted**
**No analyses by treatment comparator (e.g. placebo, active comparator)**
**Takeda has agreed to do meta-analysis for PIO similar to that done for RSG, with meta-groups by treatment comparison**

## Differences Between Rosiglitazone and Pioglitazone Clinical Trials Pools:  Implications for Overall Risk Estimates

**RSG:**
**Appr 85% pbo-controlled (where higher risk difference seen)**
**Appr 15% head-to-head against SU (where less risk seen)**

**PIO:**
**Appr 20% pbo-controlled**
**Appr 62% head-to-head against SU**

## Possible Importance of Duration of StudyTime to PROactive Primary Composite Endpoint

## Contribution of PROactive to TZD Myocardial Ischemic Event Risk Evaluation

**Long-term CV outcome trial of TZD with statistically neutral and numerically favorable results for add-on PIO**
**HF risk for add-on PIO> add-on PBO, but HF not included in endpoint composites; HF was included in DREAM and RECORD composites**
**Showed possible importance of duration of study**
**Analysis using favorable PROactive secondary endpoint also favorable in PIO pooled studies analysis**
**Takeda working with FDA to perform pooled studies meta-analysis comparable to that done for RSG**

## USE OF SIMILAR ENDPOINTS ACROSS DATA SOURCES

## Cardiovascular Mortality + Myocardial Infarction + Stroke (“MACE”)

| Data Source | Comparison and Analysis Source | “MACE”
HR 
(95% CI), p | CV Mort
HR 
(95% CI), p | MI
HR 
(95% CI), p | Stroke
HR 
(95% CI), p |
| --- | --- | --- | --- | --- | --- |
| Pooled Shorter-term DM Studies | All RSG vs 
All CONTR, 
FDA | 1.2 
(0.8, 1.8), 
p=0.4 | 1.7 
(0.7, 5.0), 
p=0.2 | 1.5 
(0.9, 2.7), 
p=0.1 | 0.6 
(0.2, 1.2), 
p=0.1 |
| ADOPT | RSG vs SU, 
FDA | 1.2 
(0.7, 1.9), 
p=0.3 | 0.6 
(0.2, 1.9), 
p=0.4 | 1.6 
(0.8, 3.1), 
p=0.2 | 0.9 
(0.4, 2.1), 
p=0.9 |
| ADOPT | RSG vs MET, 
FDA | 1.1 
(0.7, 1.8), 
p=0.6 | 1.3 
(0.4, 5.0), 
p=0.7 | 1.3 
(0.7, 2.3), 
p=0.4 | 0.8 
(0.4, 1.6), 
p=0.5 |
| DREAM | RSG vs PBO, FDA | 1.1
(0.5, 2.4),
p=1.0 | 1.0
(0.2, 4.3),
p=1.0 | 0.8
(0.2, 3.3), 
p=0.8 | 1.7
(0.3, 10.7), p=0.7 |
| DREAM | RSG + RAM vs RAM,
FDA | 2.0 
(0.9, 5.1),
p=0.1 | 1.4
(0.4, 5.6),
p=0.6 | 3.7
(0.97, 20.7),
p=0.03 | 1.0
(0.1, 13.8)
p=1.0 |

## Cardiovascular Mortality + Myocardial Infarction + Stroke (“MACE”), cont

| 
Data Source | 
Comparison and Analysis Source | 
“MACE”
HR 
(95% CI), p | 
CV Mort
HR 
(95% CI), p | 
MI
HR 
(95% CI), p | 
Stroke
HR 
(95% CI), p |
| --- | --- | --- | --- | --- | --- |
| RECORD interim | ALL RSG vs ALL CONTR, 
GSK | 0.97
(0.73, 1.29),
p=0.83 | 0.83
(0.51, 1.36),
p=0.46 | 1.16
(0.75, 1.81),
p=0.50 | np |
| PROactive | Add-on PIO vs Add-on PBO,
Takeda | 0.82
(0.70, 0.97)
p=0.02 | 0.94
(0.74, 1.20)
p=0.62 | np | 0.81
(0.61, 1.07),
p=0.14 |

## Incidence of All-Cause Mortality

| Trial | TZD | Control |
| --- | --- | --- |
| ADOPT | RSG 0.8% | SU 1.4%
MET 1.0% |
| DREAM | RSG 1.1% | PBO 1.3% |
| RECORD interim | RSG 3.3% | MET/SU combo 3.6% |
| PROactive | PIO 6.8% | PBO 7.1% |

## SUMMARY

## Similarities Between the FDA Meta-Analysis and the Large Long-Term RSG Trials

**Similar total sample size (>14,000 each)**
**All trials randomized**
**All trials controlled**
**Small numbers of events increased uncertainty of estimates**

## Differences Between FDA Meta-Analysis and Large Long-Term Trials of RSG

|  | RSG FDA Meta-Analysis of Shorter-Term Trials | RSG Longer-Term Trials |
| --- | --- | --- |
| Objectives | 41/42 glycemic control trials (not CV outcome).  1 ECHO trial. | RECORD CV outcome; DREAM and ADOPT not. |
| Heterogeneity | Pt pops, RFs, comparators, background meds, et al | BL characteristics well-matched |
| Total RSG Exposure   (pt-yrs) | Appr 4000 | Appr 20,000 |
| ?ACEI Interaction for Risk of Myocardial Ischemic Events | Yes | Yes for DREAM; not seen in ADOPT |
| Myocardial ischemic event risk | Significant increased risk for total myocardial ischemic events composite | Total myocardial ischemic events:  not signif incr
MI terms per se:  several HRs >1 |

## RECORD Interim Results

## All Cause Mortality in Long-term Clinical Trials of Rosiglitazone

## “Whatever games are played with us, we must play no games with ourselves, but deal in our privacy with the last honesty and truth.”Ralph Waldo Emerson

## Acknowledgments

**Sandra Kweder, MD, Deputy Director, OND**
**John Jenkins, MD, Director, OND**
**Hylton Joffe, MD, Acting Diabetes Team Leader, DMEP**
**John Lawrence, PhD, Biometrics Reviewer**
**Joy Mele, MS, Biometrics Reviewer**
**Robert Meyer, MD, Director, ODE II**
**Robert Misbin, MD, Medical Officer, DMEP **
**Mary Parks, MD, Director, DMEP **
**Todd Sahlroot, PhD, Biometrics Team Leader**
**Joanna Zawadzki, MD, Medical Officer, DMEP**
**Colleagues in OSE**