endocrinologic and metabolic drugs advisory committee briefing

138 Pages·2016·18.93 MB·English

ABCD

ENDOCRINOLOGIC AND METABOLIC DRUGS
ADVISORY COMMITTEE BRIEFING DOCUMENT

EMPA-REG OUTCOME® Trial

NDA 204629 / NDA 206111
Jardiance® (empagliflozin) / Synjardy® (empagliflozin/metformin)

19 May 2016
Boehringer Ingelheim

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION
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EXECUTIVE SUMMARY
Medical background (detailed in Section 1)
The risk of cardiovascular (CV) disease is increased 2 to 4-fold in patients with diabetes. Life
expectancy is shortened by 12 to 15 years in patients with diabetes and history of CV disease.
Two thirds of patients with diabetes older than 65 years die of heart disease. Heart failure is
prevalent in patients with diabetes, occurring in more than 1 in 5 patients with diabetes aged
over 65 years. The risk of heart failure is increased more than 2-fold with diabetes, and heart
failure is a major cause of cardiovascular death in patients with diabetes. Conclusive evidence
is lacking that intensive glucose lowering or any specific glucose-lowering therapy improves
CV outcome. Thus, there is a strong medical need for glucose-lowering therapies that reduce
CV complications in patients with type 2 diabetes.
The EMPA-REG OUTCOME® Trial (Sections 2 and 3)
This event-driven, multinational, randomized, double-blind, parallel-group trial compared
empagliflozin (10 mg and 25 mg pooled) with placebo in addition to standard of care in
patients with type 2 diabetes and established CV diseases. Patients with an eGFR of less than
30 mL/min/1.73m2 were excluded. At the end of the trial, primary endpoint information was
available for 97%, and vital status available for more than 99% of the 7020 trial patients.
Median observation time was 3.1 years, median treatment exposure 2.6 years.
Major findings in the EMPA-REG OUTCOME® Trial
3-point MACE and 4-point MACE (Section 5.1)
The primary endpoint (3-point MACE) was the time to first occurrence of CV death
(including fatal MI and fatal stroke), non-fatal MI, or non-fatal stroke. The key secondary
endpoint (4-point MACE) was the time to first occurrence of any component in the 3-point
MACE or hospitalization for unstable angina pectoris.
The primary analysis followed the ITT principle, based on all treated patients and included all
events up to trial completion of individual patients, regardless if the patient was on or off
study medication. Type I error was controlled for the primary and key secondary endpoints
by a 4-step hierarchical testing procedure. Other clinically important outcomes were pre-
specified, such as the components of MACE as stand-alone endpoints, all-cause mortality,
heart failure outcomes, but were not controlled for type I error with a statistical testing
strategy (nominal p-values are shown).
The confirmatory testing compared empagliflozin 10 mg and 25 mg (pooled) with placebo
treatment. The 3-point MACE outcome occurred in 490 of 4687 patients (10.5%) in the
pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard
ratio pooled empagliflozin vs. placebo 0.86; 95.02% confidence interval 0.74 to 0.99; 1-sided
p<0.0001 for non-inferiority; 2-sided p=0.0382 for superiority).
The 4-point MACE outcome occurred in 599 of 4687 patients (12.8%) in the pooled
empagliflozin group and in 333 of 2333 patients (14.3%) in the placebo group (hazard ratio
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0.89; 95.02% confidence interval 0.78 to 1.01; 1-sided p<0.0001 for non-inferiority; 2-sided
p=0.0795 for superiority).
Therefore, following the hierarchical testing procedure
• Step 1, non-inferiority for 3-point MACE was concluded because the upper bound
of the 2-sided 95.02% CI was <1.3 (upper bound 95.02% CI = 0.99; 1-sided
p<0.0001 for non-inferiority)
• Step 2, non-inferiority for 4-point MACE was concluded because the upper bound
of the 2-sided 95.02% CI was <1.3 (upper bound 95.02% CI = 1.01; 1-sided
p<0.0001 for non-inferiority)
• Step 3, superiority for 3-point MACE was concluded because the upper bound of
the 2-sided 95.02% CI was <1.0 (upper bound 95.02% CI = 0.99; 2-sided
p=0.0382 for superiority)
• Step 4, superiority for 4-point MACE was not concluded because the upper bound
of the 2-sided 95.02% CI was >1.0 (upper bound 95.02% CI = 1.01; 2-sided
p=0.0795)

The results for 3-point MACE were consistent for both empagliflozin doses and across
sensitivity analyses in that the hazard ratio was numerically similar, although due to the fewer
events in these analyses, the nominal p-value did not reach significance (p>0.05). Some
heterogeneity was observed in 2 (by age and HbA ) of the 27 pre-specified subgroups. The
1c
treatment effect for 3-point MACE was driven by CV death, with no significant difference in
non-fatal myocardial infarction (MI) or non-fatal stroke.

Myocardial infarction (fatal/non-fatal) was reported for 223 (4.8%) patients in the pooled
empagliflozin group and in 126 (5.4%) patients in the placebo group (hazard ratio 0.87; 95%
confidence interval 0.70 to 1.09; nominal p=0.2302). Stroke (fatal/non-fatal) was reported for
164 (3.5%) patients in the pooled empagliflozin group and in 69 (3.0%) patients in the
placebo group (hazard ratio 1.18; 95% confidence interval 0.89 to 1.56; nominal p= 0.2567).
The additional component in 4-point MACE, hospitalization for unstable angina pectoris,
showed no significant difference between empagliflozin and placebo treatment (reported for
133 (2.8%) patients in the pooled empagliflozin group, 66 (2.8%) patients in the placebo
group; hazard ratio 0.99, 95% CI 0.74 to 1.34, nominal p=0.9706).

CV death (Section 5.1.2)
Empagliflozin significantly reduced CV death by 38%. CV death occurred in 172 of 4687
patients (3.7%) in the pooled empagliflozin group and in 137 of 2333 patients (5.9%) in the
placebo group (hazard ratio 0.62; 95% confidence interval 0.49 to 0.77; nominal p<0.0001).
The reduction in CV death was based on a large number of events (309 CV deaths in total),
consistent for both empagliflozin doses, across sensitivity analyses (including a “worst-case”
analysis assuming all patients with missing final vital status in the empagliflozin groups as
deceased due to CV death and all in the placebo group as alive), and across all subgroups. All
categories of CV death (fatal MI, fatal stroke, death due to heart failure, sudden death, death
due to other CV causes, and presumed CV death) contributed to the overall CV death results.
The hazard ratios for these categories of CV death were consistently around 0.7, except death
due to heart failure (hazard ratio 0.32).
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Heart failure (Section 5.2)
Heart failure endpoints were pre-specified in this trial. Empagliflozin significantly reduced
hospitalization for heart failure by 35% and the composite endpoint of hospitalization for
heart failure or CV death by 34%. The composite of “hospitalization for heart failure or CV
death” occurred in 265 of 4687 patients (5.7%) in the pooled empagliflozin group and in 198
of 2333 patients (8.5%) in the placebo group (hazard ratio 0.66; 95% confidence interval 0.55
to 0.79; nominal p<0.0001). These results were consistent for both empagliflozin doses,
across sensitivity analyses, and across subgroups (including patients with or without a history
of heart failure at baseline).
All-cause mortality (Section 5.3)
Empagliflozin significantly reduced all-cause mortality (a pre-specified endpoint) by 32%.
All-cause mortality occurred in 269 of 4687 patients (5.7%) in the pooled empagliflozin
group and in 194 of 2333 patients (8.3%) in the placebo group (hazard ratio 0.68; 95%
confidence interval 0.57 to 0.82; nominal p<0.0001). The results were based on a large
number of events (463 total deaths), consistent for both empagliflozin doses, across
sensitivity analyses (including a “worst-case” analysis assuming all patients with missing
final vital status in the empagliflozin groups as deceased and all in the placebo group as
alive), and across subgroups. Most of the deaths in the trial were CV deaths, the most
frequent cause of death in patients with type 2 diabetes. Non-CV death occurred in 97 of
4687 patients (2.1%) in the pooled empagliflozin group and in 57 of 2333 patients (2.4%) in
the placebo group (hazard ratio 0.84, 95% CI 0.60 to 1.16, nominal p=0.2852).
General safety (Section 6)
The frequencies of adverse events, serious adverse events, and adverse events leading to
treatment discontinuation were comparable in the placebo, empagliflozin 10 mg, and
empagliflozin 25 mg groups. The frequencies of adverse events of special interest, including
volume depletion, decreased renal function, venous embolic and thrombotic events, diabetic
ketoacidosis, bone fracture, and hypoglycaemia were comparable in the 3 treatment groups.
Genital infections were increased with empagliflozin (10 mg or 25 mg) treatment. The
frequencies of overall malignancy events and subtypes of interest (such as bladder, kidney,
and breast cancer) were comparable for empagliflozin (10 mg or 25 mg) and placebo. These
results are consistent with the known safety profile of empagliflozin. While a natural decline
in renal function expressed as eGFR over the observation period was seen in patients treated
with placebo, eGFR was stable over time in patients treated with empagliflozin (10 mg or
25 mg).
Overall benefit-risk and discussion of the major findings (Section 7.2)
There is a clear unmet medical need for glucose-lowering therapies to reduce CV morbidity
and mortality. Before the results of the EMPA-REG OUTCOME® trial, no clinical study with
any glucose-lowering drug had established conclusive evidence of risk reduction in
cardiovascular complications. To inform prescribers, Boehringer Ingelheim is proposing to
revise empagliflozin’s label based on the EMPA-REG OUTCOME® trial.
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Added to standard of care, empagliflozin significantly reduced the risk of the 3-point MACE
(the pre-defined primary endpoint controlled for type 1 error) by 14% compared with
placebo, fulfilling the requirements in the FDA guidance document on evaluating
cardiovascular risk and the post-marketing requirement. This was driven by a significant
reduction in CV death of 38%, while no significant effects on the atherosclerotic components
of the 3-point MACE, non-fatal MI and non-fatal stroke, were observed.
The CV death results are considered clinically important and statistically robust, as CV death
was a component of the primary confirmatory endpoint, pre-specified, centrally-adjudicated
in a blinded manner, based on large numbers of events, and the results are consistent across
individual empagliflozin doses, sensitivity analyses (including the “worst-case” analysis), and
subgroups. The treatment effect was also supported by a statistically persuasive p-value of
<0.0001 (nominal), ensuring a replication probability of >98% for the result. Boehringer
Ingelheim therefore proposes to include in the prescribing information that in adult patients
with type 2 diabetes mellitus and established cardiovascular disease, empagliflozin is
indicated to reduce the incidence of cardiovascular death.
The EMPA-REG OUTCOME® trial was designed to assess the effects of empagliflozin on
clinical outcomes rather than the mechanism behind the effects. Nonetheless, the results
suggest that the underlying mechanism for the CV death benefit is at least in part
hemodynamic in nature rather than atherothrombotic. Specifically, 1) a significant (nominal
p=0.0017) and clinically-relevant reduction (35%) in the risk of hospitalization for heart
failure was observed with empagliflozin treatment; 2) the benefit of empagliflozin on both
CV death and hospitalization for heart failure emerged rapidly after randomization; 3) the
hazard ratio for death due to heart failure (0.32) was lower than for the other categories of CV
death (around 0.7 for fatal MI, fatal stroke, sudden death, death due to other CV causes, and
presumed CV death); 4) no significant effects of empagliflozin were observed for non-fatal
MI and non-fatal stroke.
Importantly, the risk reduction in CV death with empagliflozin was not associated with an
increase in non-CV mortality. In fact, empagliflozin treatment significantly reduced all-cause
mortality by 32%. All-cause mortality is a unique and exceptionally compelling endpoint,
since it is unbiased in ascertainment and is of paramount clinical importance. The all-cause
mortality result in the trial was based on a large number of events: 463 total deaths. In this
trial vital status was ascertained for >99% of the 7020 trial patients, and the results remain
highly significant even in a worst-case analysis assuming all patients with missing final vital
status on empagliflozin as deceased and all on placebo as alive.
Empagliflozin was well tolerated, and the safety results in this trial are consistent with the
known safety profile of empagliflozin.
The benefit-risk is positive for empagliflozin 10 mg and 25 mg once daily treatment in
patients with type 2 diabetes mellitus, established CV disease, and eGFR
≥30 mL/min/1.73 m2.
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TABLE OF CONTENTS
TITLE PAGE ........................................................................................................................... 1
EXECUTIVE SUMMARY ..................................................................................................... 2
TABLE OF CONTENTS ........................................................................................................ 6
LIST OF ABBREVIATIONS ................................................................................................. 9
1. INTRODUCTION ............................................................................................... 11
1.1 PURPOSE OF THIS DOCUMENT .................................................................. 11
1.2 MEDICAL BACKGROUND OF TYPE 2 DIABETES................................... 11
1.3 EMPAGLIFLOZIN DRUG PROFILE AND REGULATORY STATUS ..... 12
1.4 EVALUATION OF CV SAFETY IN NEW GLUCOSE-LOWERING
AGENTS .............................................................................................................. 12
2. DESIGN OF THE EMPA-REG OUTCOME® TRIAL ................................... 13
2.1 TRIAL GOVERNANCE .................................................................................... 13
2.2 TRIAL DESIGN .................................................................................................. 14
2.3 ENDPOINTS AND STATISTICAL METHODS ............................................ 15
2.4 INTERIM ANALYSIS ....................................................................................... 18
3. TRIAL POPULATION CHARACTERISTICS .............................................. 18
3.1 PATIENT DISPOSITION .................................................................................. 18
3.2 DEMOGRAPHIC AND BASELINE DATA .................................................... 19
3.3 EXPOSURE ......................................................................................................... 19
3.4 POST-BASELINE CONCOMITTANT MEDICATION ................................ 20
4. EFFECTIVENESS MARKERS ........................................................................ 20
5. CARDIOVASCULAR RESULTS ..................................................................... 20
5.1 MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) ................... 20
5.1.1 Primary and key secondary endpoints: 3-point MACE and 4-point MACE 20
5.1.2 Cardiovascular (CV) death ................................................................................ 23
5.1.3 Myocardial infarction (MI)-related outcomes .................................................. 26
5.1.4 Cerebrovascular disease-related outcomes (stroke and TIA) ......................... 26
5.2 HEART FAILURE OUTCOMES ..................................................................... 29
5.3 ALL-CAUSE MORTALITY ............................................................................. 32
5.4 SUMMARY OF CARDIOVASCULAR RESULTS ........................................ 34
6. GENERAL SAFETY RESULTS ....................................................................... 36
6.1 OVERALL ADVERSE EVENTS ...................................................................... 37
6.2 ADVERSE EVENTS OF SPECIAL INTEREST ............................................ 37
6.2.1 Urinary tract infection ........................................................................................ 39
6.2.2 Genital infection .................................................................................................. 39
6.2.3 Volume depletion................................................................................................. 40
6.2.4 Venous embolic and thrombotic events ............................................................ 40
6.2.5 Diabetic ketoacidosis adverse events ................................................................. 40
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6.2.6 Bone fracture ....................................................................................................... 41
6.2.7 Malignancy .......................................................................................................... 41
6.2.8 Hepatic injury ...................................................................................................... 41
6.2.9 Hypoglycemic events ........................................................................................... 42
6.2.10 Hypersensitivity ................................................................................................... 42
6.3 RENAL SAFETY ................................................................................................ 42
6.3.1 Decreased renal function reported as adverse events ...................................... 42
6.3.2 Renal outcome and eGFR over time ................................................................. 43
6.4 SUMMARY OF GENERAL SAFETY RESULTS .......................................... 45
7. SUMMARY AND DISCUSSION ...................................................................... 45
7.1 SUMMARY OF THE EMPA-REG OUTCOME® TRIAL RESULTS.......... 45
7.2 OVERALL BENEFIT-RISK AND DISCUSSION OF THE MAJOR
FINDINGS ........................................................................................................... 47
8. SUPPLEMENTARY TABLES AND FIGURES ............................................. 49
8.1 TRIAL INFORMATION: COMMITTEE MEMBERS, INCLUSION
AND EXCLUSION CRITERIA ........................................................................ 49
8.2 DEMOGRAPHIC AND BASELINE DATA - TS ............................................ 53
8.3 OBSERVATIONAL PERIOD AND TREATMENT EXPOSURE ................ 55
8.4 MEDICATIONS INTRODUCED POST-BASELINE - TS ............................ 56
8.5 EFFECTIVENESS MARKERS RESULTS ..................................................... 57
8.6 HEART RATE RESULTS ................................................................................. 58
8.7 SERUM LIPIDS RESULTS ............................................................................... 59
8.8 PRIMARY ENDPOINT: 3-POINT MACE RESULTS .................................. 60
8.9 KEY SECONDARY ENDPOINT: 4-POINT MACE RESULTS ................... 64
8.10 CV DEATH RESULTS ...................................................................................... 64
8.11 MI-RELATED RESULTS ................................................................................. 69
8.12 CEREBROVASCULAR DISEASE-RELATED RESULTS (STROKE
AND TIA)............................................................................................................. 72
8.13 HEART FAILURE RESULTS .......................................................................... 83
8.14 ALL-CAUSE MORTALITY RESULTS .......................................................... 90
8.15 MOST FREQUENT ADVERSE EVENTS....................................................... 96
8.16 URINARY TRACT INFECTION (BICMQ) RESULTS .............................. 101
8.17 GENITAL INFECTION (BICMQ) RESULTS .............................................. 104
8.18 VOLUME DEPLETION (BICMQ) RESULTS ............................................. 107
8.19 VENOUS EMBOLIC AND THROMBOTIC EVENTS (SMQ) – TS .......... 108
8.20 HEMATOLOGY RESULTS ........................................................................... 109
8.21 BONE FRACTURE (BICMQ) RESULTS ..................................................... 110
8.22 MALIGNANCY (SMQ) UP TO TRIAL TERMINATION – TS ................. 112
8.23 HEPATIC INJURY (SMQ) RESULTS .......................................................... 113
8.24 CONFIRMED HYPOGLYCEMIC AES BY SUBGROUPS - TS................ 115
8.25 HYPERSENSITIVITY (SMQ) RESULTS ..................................................... 117
8.26 DECREASED RENAL FUNCTION (SMQ) RESULTS ............................... 118
8.27 ELECTROLYTES MEAN (SD) VALUES - TS............................................. 119
8.28 RENAL OUTCOME RESULTS ..................................................................... 120
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8.29 CEC CHARTER: ADJUDICATION PROCESS AND CLINICAL
EVENTS DEFINITIONS ................................................................................. 121
9. LITERATURE REFERENCES ...................................................................... 135
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LIST OF ABBREVIATIONS
ACEi Angiotensin converting enzyme inhibitors
AE Adverse event
AESI Adverse event of special interest
ALT Alanine aminotransferase
ARB Angiotensin receptor blocker
AST Aspartate aminotransferase
BI Boehringer Ingelheim
BICMQ BI-customized MedDRA query
BMI Body mass index
BNP Brain natriuretic peptide
BP Blood pressure
CAD Coronary artery disease
CEC Clinical Event Committee
CI Confidence interval
CKD Chronic kidney disease
CKD-EPI Chronic kidney disease epidemiology collaboration
CV Cardiovascular
DBP Diastolic blood pressure
DPP-4 Dipeptidyl peptidase 4
ECG Electrocardiogram
eGFR (Estimated) glomerular filtration rate
EMA European Medicines Agency
Empa Empagliflozin
EMPA-REG OUTCOME® EMPAgliflozin Removal of Excess of Glucose OUTCOME trial
FAS Full analysis set
FDA Food and Drug Administration
FPG Fasting plasma glucose
FU Follow up
HbA Glycosylated hemoglobin
1c
HDL High-density lipoprotein
HHF Hospitalization for heart failure
HLT High level term
HR Hazard ratio
ITT Intent to treat
LDL Low-density lipoprotein
LVOT Last value on-treatment
MACE Major adverse cardiovascular events
MDRD Modification of diet in renal disease
MedDRA Medical dictionary for drug regulatory activities
MI Myocardial infarction
MMRM Mixed model repeated measures
MRA Mineralocorticoid receptor antagonist
NNT Number needed to treat
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OC-AD Observed cases after treatment discontinuation or after rescue
medication intake (following the ITT principle)
OR Original results
OS On-treatment set
PT Preferred term
pt-yrs Patient-years
SBP Systolic blood pressure
SD Standard deviation
SE Standard error
SGLT Sodium-dependent glucose co-transporter
SMQ Standardized MedDRA query
SOC System organ class
SU Sulphonylurea
T2DM Type 2 diabetes mellitus
TIA Transient ischemic attack
TS Treated set
UACR Urine albumin-to-creatinine ratio
ULN Upper limit of normal
UTI Urinary tract infection