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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`201280Orig1s000
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`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`STATISTICAL REVIEW AND EVALUATION
`CLINICAL STUDIES
`
`
`
`NDA/Serial Number:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`Review Priority:
`
`201-280 / SN 000
`Tardjenta 1 (Linagliptin, BI 1356)
`Treatment of patients with type 2 diabetes mellitus
`Boehringer Ingelheim Pharmaceuticals Inc
`Submitted July 2, 2010
`Standard
`
`Biometrics Division:
`Division of Biometrics VII
`Statistical Reviewer:
`Xiao Ding, Ph.D.
`Concurring Reviewers: Mat Soukup, Ph.D.
`
`Aloka Chakravarty, Ph.D.
`
`
`Medical Division:
`Division of Metabolism and Endocrinology Products (DMEP)
`Clinical Team:
`Medical Officer: Somya (Verma) Dunn, M.D.
`Medical Team Leader: Ilan Irony, M. D.
`Project Manager:
`Raymond Chiang, M.S. (DMEP)
`
`
`
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`Keywords: clinical studies, cardiovascular safety, meta-analysis
`
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`
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`1 At the time of filing of this review, the trade name under review is Tardjenta, but DMEPA has not
`reached a decision on the adequacy of such trade name.
`
`Reference ID: 2918087
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`

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`NDA 201-280 (Tardjenta) Page 2 of 48
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`2
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`Table of Contents
`
`1 Executive Summary.....................................................................................5
`1.1
`Conclusions and Recommendations................................................................ 5
`1.2
`Brief Overview of Clinical Studies .................................................................. 6
`1.3
`Statistical Issues and Findings......................................................................... 6
`Introduction..................................................................................................8
`2.1
`Product Description.......................................................................................... 8
`2.2
`Clinical Trial Overview.................................................................................... 8
`2.3
`Data Sources...................................................................................................... 8
`3 Statistical Evaluation...................................................................................9
`3.1
`Evaluation of Safety.......................................................................................... 9
`3.1.1 Study Designs ................................................................................................. 9
`3.1.2 Statistical Methodologies.............................................................................. 11
`3.1.2.1 Methods of Imputing Missing......................................................................... 11
`3.1.2.2 Analysis of Event Incidence ........................................................................... 12
`3.1.2.3
`Time-to-Event Analysis .................................................................................. 12
`3.1.2.4 Handling of Trials with zero events................................................................ 12
`3.1.3 Populations.................................................................................................... 13
`3.1.4 Subject Disposition, Demographic and Baseline Characteristics................. 15
`3.1.5 Endpoints ...................................................................................................... 20
`3.1.5.1
`Primary Composite Endpoints ........................................................................ 20
`3.1.5.2
`Secondary Endpoints ...................................................................................... 20
`3.1.6 Results and Conclusions ............................................................................... 21
`3.1.6.1
`Primary Composite Endpoint.......................................................................... 21
`3.1.6.1.1 Analysis of Incidence ............................................................................................. 21
`3.1.6.1.2 Sensitivity Analyses of Incidence .......................................................................... 22
`3.1.6.1.3 Forest Plot of All Results for Primary Composite Endpoint .................................. 24
`3.1.6.1.4 Time-to-Event Analysis of Primary composite endpoint ....................................... 25
`3.1.6.1.5 Sensitivity Time-to-Event Analyses....................................................................... 26
`3.1.6.2
`Secondary Endpoint........................................................................................ 28
`4 Findings in Special/Subgroup Populations.............................................32
`4.1 Gender, Race, and Age................................................................................... 32
`4.2 Other Special/Subgroup Populations............................................................ 33
`4.2.1 Ethnicity........................................................................................................ 33
`4.2.2 Baseline BMI ................................................................................................ 34
`4.2.3 Baseline Renal Impairment Status................................................................ 34
`4.3
`Summary Forest Plot for all Subgroup Analysis Results............................ 34
`5 Summary and Conclusions.......................................................................35
`5.1
`Statistical Issues and Collective Evidence .................................................... 35
`5.2
`Conclusions and Recommendations.............................................................. 35
`Appendix ...........................................................................................................38
`A.1 Supplementary Tables......................................................................................... 38
`A.2 Supplementary Figures ....................................................................................... 44
`Signatures/Distribution List.............................................................................48
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 3 of 48
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`Table of Tables
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`Table 1: Summary of Design Characteristics for Randomized Phase 3 Trials................... 8
`Table 2: Summary of Treatment Distribution in the ITT Population by Trial ................. 14
`Table 3: Treatment Distribution in Safety Population, FAS Population, and Placebo-
`Controlled Subset of Safety Population............................................................................ 15
`Table 4: Baseline Demographics by Treatment Group (Safety Population) .................... 15
`Table 5: Baseline CV Risk Factors and Complications by Treatment Group (Safety
`Population)........................................................................................................................ 17
`Table 6: Baseline Framingham Risk by Study and Treatment Group (Safety Population)
`........................................................................................................................................... 18
`Table 7: Premature Discontinuation of Study Medication by Study and Treatment Group
`(FAS Population) .............................................................................................................. 20
`Table 8: Summary of Events of Primary Composite Endpoint by Study and Treatment
`Group (Safety Population) ................................................................................................ 21
`Table 9: Meta-analysis Results of Primary Composite Endpoint (Safety Population)..... 22
`Table 10: Sensitivity Meta-Analysis Results of Primary Composite Endpoint (Safety
`Population Excluding Study 1218.20) .............................................................................. 23
`Table 11: Summary of Events of Primary Composite Endpoint by Study and Treatment
`Group (Placebo-Controlled Subset of Safety Population)................................................ 23
`Table 12: Sensitivity Meta-analysis Results of Primary Composite Endpoint (Placebo-
`Controlled Subset of Safety Population)........................................................................... 24
`Table 13: Summary of Events of MACE by Study and Treatment Group (Safety
`Population)........................................................................................................................ 29
`Table 14: Meta-Analysis Results of Secondary Endpoints (Safety Population) .............. 30
`Table 15: Summary of Events of Primary Composite Safety Endpoint by Gender, Study
`and Treatment Group (Safety Population)........................................................................ 38
`Table 16: Summary of Events of Primary Composite Safety Endpoint by Race, Study and
`Treatment Group (Safety Population)............................................................................... 39
`Table 17: Summary of Events of Primary composite endpoint by Age Categories, Study
`and Treatment Group (Safety Population)........................................................................ 40
`Table 18: Summary of Events of Primary composite endpoint by Ethnicity, Study and
`Treatment Group (Safety Population)............................................................................... 41
`Table 19: Summary of Events of Primary composite endpoint by Baseline BMI, Study
`and Treatment Group (Safety Population)........................................................................ 42
`Table 20: Summary of Events of Primary composite endpoint by Baseline Renal
`Impairment Status, Study and Treatment Group (Safety Population) .............................. 43
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 4 of 48
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`Table of Figures
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`Figure 1: Percentage of Subjects with Premature Discontinuation of Study Medication by
`Study and Treatment Group (FAS Population) ................................................................ 19
`Figure 2: Forest Plot of Reviewer’s Analysis Results of Primary Composite Endpoint
`(Risk difference) ............................................................................................................... 25
`Figure 3: Time to Event Analysis of the Primary Composite Endpoint (Safety Population,
`Double-Blind Treatment Phase) ....................................................................................... 26
`Figure 4: Time to Event Analysis of the Primary composite endpoint Excluding Study
`1218.20 (Safety Population, Double-Blind Treatment Phase).......................................... 27
`Figure 5: Time to Event Analysis of the Primary composite endpoint (Placebo-Controlled
`Trials, Safety Population, Double-Blind Placebo-Controlled Phase)............................... 28
`Figure 6: Forest Plot of Reviewer’s Analysis Results of Secondary Endpoints (M-H Risk
`difference)......................................................................................................................... 31
`Figure 7: Forest Plot of Reviewer’s Analysis Results of Subgroups (M-H Risk
`Difference) ........................................................................................................................ 35
`Figure 8: Forest Plot of Reviewer’s Analysis Results of Primary composite endpoint (M-
`H Relative Risk)................................................................................................................ 44
`Figure 9: Forest Plot of Reviewer’s Analysis Results of Primary composite endpoint
`(Exact Odds Ratio)............................................................................................................ 45
`Figure 10: Forest Plot of Reviewer’s Analysis Results of Secondary Endpoints (M-H
`Relative Risk).................................................................................................................... 46
`Figure 11: Forest Plot of Reviewer’s Analysis Results of Subgroups (M-H Relative Risk)
`........................................................................................................................................... 47
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 5 of 48
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`1 Executive Summary
`
`This statistical review and evaluation was performed in response to a consultation from
`the Division of Biometrics 2 (DB2) for New Drug Application (NDA) 201-280/000
`(received August 9, 2010) for linagliptin tablets. The proposed indication for linagliptin is
`the treatment of patients with type 2 diabetes mellitus. This statistical review assesses
`cardiovascular (CV) related safety endpoints in the randomized phase 3 clinical
`development program of linagliptin (Studies 1218.15, 1218.16, 1218.17, 1218.18,
`1218.20, 1218.23, 1218.35, and 1218.50). A separate efficacy evaluation is also being
`reviewed by Dr. Wei Liu from DB2. This review focuses solely on safety evaluation.
`1.1 Conclusions and Recommendations
`
`Among the 8 randomized phase 3 trials for linagliptin, the trial design characteristics of
`Study 1218.20 differed from the other 7 trials (the only glimepiride-controlled trial, the
`only non-inferiority trial, and had the longest duration), and the study population in Study
`1218.20 appeared to have higher baseline CV risk than all other trials. Therefore,
`utilizing data from Study 1218.20 and its contribution to a meta-analysis may be
`problematic. Due to the fact that Study 1218.20 was the only glimepiride-controlled trial,
`extra caution is needed when interpreting the results of the comparison between the
`linagliptin group and the pooled all comparator group.
`
`Based on the meta-analysis of all 8 randomized phase 3 trials, the incidence of CV related
`events measured utilizing an agreed upon primary composite CV safety endpoint
`(composite of CV death, non-fatal myocardial
`infarction, non-fatal stroke, or
`hospitalization due to unstable angina) was found to be statistically significantly lower in
`the linagliptin group than in the pooled all comparator group (glimepiride, voglibose, or
`placebo) at the nominal α=0.05 level. The M-H risk difference between linagliptin and all
`comparator was -0.69% with a 95% confidence interval of (-1.17%, -0.21%). However,
`the results of the meta-analysis were heavily driven by Study 1218.20. One sensitivity
`analysis showed that, without Study 1218.20, the incidence of the primary composite
`endpoint was higher in the linagliptin group than in the all comparator group (voglibose
`or placebo) but the difference was not statistically significant. The M-H risk difference
`between linagliptin and all comparator was 0.06% with a 95% CI of (-0.34%, 0.46%).
`Furthermore, based on the placebo-controlled subset of the trials, another sensitivity
`analysis found no statistically significant difference between linagliptin and placebo in
`the incidence of primary composite endpoint. The M-H risk difference between
`linagliptin and placebo was -0.04% with a 95% CI of (-0.45%, 0.37%).
`
`In Study 1218.20 also, as compared to glimepiride, linagliptin was shown to be
`associated with statistically significantly lower risk in developing a CV related event as
`measured by the primary composite endpoint. The majority of events observed in the
`phase 3 program for linagliptin were from Study 1218.20 and this in turn impacted the
`meta-analysis of the 8 trials comparing linagliptin to all comparators. Therefore, no
`definite conclusion can be reached on the CV safety of linagliptin in relation to a placebo
`or alternative active control other than glimepiride.
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 6 of 48
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`1.2 Brief Overview of Clinical Studies
`
`In this NDA application, the applicant submitted 8 randomized phase 3 trials, Study
`1218.15, Study 1218.16, Study 1218.17, Study 1218.18, Study 1218.20, Study 1218.23,
`Study 1218.35, and Study 1218.50, in support of the safety and efficacy of linagliptin for
`the treatment of type 2 diabetes mellitus.
`
`All 8 randomized phase 3 trials were conducted in subjects with type 2 diabetes mellitus.
`Studies 1218.15, 1218.16, 1218.17, and 1218.18 were all multicenter, randomized,
`double-blinded, placebo-controlled, pivotal trials to compare the safety and efficacy of
`linagliptin and placebo for 24 weeks of treatment. Study 1218.20 was a multicenter,
`randomized, double-blinded, active-controlled, non-inferiority trial to compare the safety
`and efficacy of linagliptin and glimepiride for 104 weeks of treatment. Study 1218.23
`was a multicenter, randomized, double-blinded, placebo-/active- controlled trial to
`compare the safety and efficacy of linagliptin and placebo for 12 weeks of treatment, and
`to compare the safety and efficacy of linagliptin and voglibose for 26 weeks of treatment.
`Study 1218.35 was a multicenter, randomized, double-blinded, placebo-controlled trial to
`compare the safety and efficacy of linagliptin and placebo for 18 weeks of treatment.
`Study 1218.50 was a multicenter, randomized, double-blinded, placebo-controlled trial to
`compare the safety and efficacy of linagliptin and placebo for 18 weeks of treatment
`(with a 34 week extension period).
`
`In the pooled data base of the 8 randomized phase 3 trials, a total of 3,322 subjects were
`randomized to receive linagliptin, while a total of 979 subjects were randomized to
`receive placebo, and a total of 943 subjects were randomized to receive active comparator
`(781 to glimepiride and 162 to voglibose). Details of the 8 randomized phase 3 trials are
`provided in Section 3.1.1.
`1.3 Statistical Issues and Findings
`
`The primary agreed upon safety endpoint was a composite endpoint made up by CV
`death, non-fatal myocardial infarction (MI), non-fatal stroke, and hospitalization due to
`unstable angina.
`
`Phase 3 data from the 8 randomized studies were pooled to evaluate the risk of
`developing a CV related event as measured by the primary composite endpoint. In this
`review, the comparison of incidence between the linagliptin group and the pooled all
`comparator group (including comparators of glimepiride, voglibose, or placebo) was
`performed using the Mantel-Haenszel (M-H) risk difference approach with study as
`stratification factor. The M-H relative risk ratio approach and the exact stratified odds
`ratio approach were also applied to evaluate the relative risk ratio or odds ratio of
`linagliptin. Stratified log-rank test and stratified Cox proportional hazards regression
`model were performed for the time-to-event analyses. More details for the statistical
`methodologies used in this review are provided in Section 3.1.2.
`
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 7 of 48
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`Based on the pooled data of all 8 randomized phase 3 trials, a total of 34 events of the
`primary composite endpoint were reported, 11 occurred in the linagliptin group and 23
`occurred in the pooled all comparator group. The incidence of the primary composite
`endpoint was 0.33% (11/3319) in the linagliptin group, as compared to 1.20% (23/1920)
`in the all comparator group. The M-H risk difference between linagliptin and all
`comparator was -0.69% with a 95% confidence interval (CI) of (-1.17%, -0.21%). The
`M-H relative risk ratio between linagliptin and all comparator was 0.34 with a 95% CI of
`(0.15, 0.74), and similar results were seen for the exact stratified odds ratio. Detailed
`analysis results are provided in Section 3.1.6.1.1 and Section 3.1.6.1.4.
`
`The meta-analysis results for the primary composite endpoint were heavily driven by
`Study 1218.20. Because Study 1218.20 had different trial design characteristics than the
`other 7 trials (the only glimepiride-controlled trial, the only non-inferiority trial, and had
`the longest duration), and the study population in Study 1218.20 appeared to have higher
`baseline CV risk than all other trials, the heavy impact of Study 1218.20 on the overall
`meta-analysis results is of concern. Among the total of 23 events of the primary
`composite endpoint reported in the pooled all comparator group, 20 occurred in the
`glimepiride arm in Study 1218.20. Therefore, two sensitivity analyses were performed to
`assess the robustness of the meta-analysis results. Without Study 1218.20, the incidence
`of the primary composite endpoint was 0.31% (8/2541) in the linagliptin group, as
`compared to 0.26% (3/1139) in the all comparator group. The M-H risk difference
`between linagliptin and all comparator was 0.06% with a 95% CI of (-0.34%, 0.46%),
`and the M-H relative risk ratio of linagliptin was 1.21 with a 95% CI of (0.35, 4.26).
`Furthermore, direct comparison between linagliptin and placebo was evaluated based on
`the placebo-controlled subset of the randomized phase 3 trials. The incidence rate of
`primary composite endpoint was 0.24% (6/2541) in the linagliptin group, as compared to
`0.31% (3/977) in the placebo group. The M-H risk difference between linagliptin and
`placebo was -0.04% with a 95% CI of (-0.45%, 0.37%), and the M-H relative risk ratio of
`linagliptin was 0.86 with a 95% CI of (0.23, 3.26). Detailed sensitivity analysis results
`are provided in Section 3.1.6.1.2 and Section 3.1.6.2.4.
`
`Several secondary endpoints were also evaluated in this review, including custom major
`adverse cardiovascular event (MACE) and each component of the primary composite
`endpoint. The results for MACE or non-fatal stroke were both close to the results for the
`primary composite endpoint. Results for other secondary endpoints (CV death, non-fatal
`MI, and hospitalization due to unstable angina) were in the same direction as the primary
`composite endpoint, but did not reach statistical significance. Detailed analysis results for
`the secondary endpoints are provided in Section 3.1.6.2.
`
`The difference between linagliptin and all comparator in developing a CV related event
`as measured by the primary composite endpoint were also evaluated in several
`subgroups. Most of the subgroup analysis results were in the same direction as the overall
`result for the primary composite endpoint. Detailed results for subgroup analyses are
`provided in Section 4.
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 8 of 48
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`2 Introduction
`2.1 Product Description
`
`Linagliptin is a selective, orally administered, xanthine-based Dipeptidyl-dipeptidase-4
`(DPP-4) inhibitor. The proposed indication of linagliptin is to improve glycemic control
`in adults with type 2 diabetes mellitus as an adjunct to diet and exercise. The proposed
`therapeutic dose of linagliptin is 5 mg.
`2.2 Clinical Trial Overview
`
`The applicant submitted the results of 4 large phase 3 pivotal, double-blind, placebo-
`controlled trials (Studies 1218.15, 1218.16, 1218.17, and 1218.18) with duration of
`treatment of 24 weeks in support of the safety and efficacy of Linagliptin for treatment of
`type 2 diabetes mellitus. The applicant also provided 4 additional phase 3 trials for
`further evidence: a double-blind active-controlled trial that provides long-term efficacy
`data (Study 1218.20), 2 studies with double-blind placebo-controlled treatment periods of
`18 weeks duration (Studies 1218.35 and 1218.50), and a placebo- and active-controlled
`study with an extension period which provides efficacy data over 52 weeks (Study
`1218.23). The summary of design characteristics of these 8 trials is presented in Table 1.
`
`Reviewer’s comment: Another submitted phase 3 trial (Study 1218.40) was an open-label
`extension trial of the four pivotal trials (Studies 1218.15, 1218.16, 1218.17 and 1218.18),
`therefore was not evaluated in this review. The meta-analyses in this review are focused
`on the 8 randomized phase 3 trials.
`
`
`Table 1: Summary of Design Characteristics for Randomized Phase 3 Trials
`
`
`Study Size Duration Comparison
`Study Name Treatment Arms
`1218.15
`389
`24 weeks
`Superiority
`linagliptin, placebo
`Superiority
`1218.16
`503
`24 weeks
`linagliptin, placebo
`Superiority
`1218.17
`701
`24 weeks
`linagliptin, placebo
`Superiority
`1218.18
`1058
`24 weeks
`linagliptin, placebo
`104 weeks Non-inferiority
`1218.20
`linagliptin, glimepiride
`1560
`Superiority
`1218.23
`linagliptin, placebo, voglibose
`561
`26 weeks *
`Superiority
`1218.35
`245
`18 weeks
`linagliptin, placebo
`Superiority
`1218.50
`227
`18 weeks**
`linagliptin, placebo
`* With a 26 week extension period after the 26 week double-blinded phase
`** With a 34 week active-controlled extension period after the 18 week placebo-controlled phase
`Source: Created by reviewer.
`2.3 Data Sources
`
`The applicant submitted electronic documents and datasets for Studies 1218.15, 1218.16,
`1218.17, 1218.18, 1218.20, 1218.23, 1218.35 and 1218.50. The following files available
`within the CDER Electronic Document Room (EDR) were utilized in this review.
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 9 of 48
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`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0015
`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0016
`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0017
`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0018
`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0020ia
`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0023
`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0035
`\\Cdsesub1\evsprod\NDA201280\0000\m5\datasets\1218-0050ia
`\\Cdsesub1\evsprod\NDA201280\0017\m5\datasets\u10-1736\analysis
`3 Statistical Evaluation
`
`This review is focused on the meta-analysis of cardiovascular (CV) risk. For a complete
`statistical evaluation of efficacy results, please refer to the review authored by Dr. Wei
`Liu.
`3.1 Evaluation of Safety
`
`The review of CV safety comprises data from Studies 1218.15, 1218.16, 1218.17,
`1218.18, 1218.20, 1218.23, 1218.35, and 1218.50. Based upon interactions with the
`clinical review team, the following review of safety consists of a focused evaluation of
`CV endpoints. All comparative analyses are between the randomized treatment groups,
`linagliptin and comparator, or linagliptin and placebo.
`3.1.1 Study Designs
`
`Study 1218.15 was a phase 3 multicenter, randomized, double-blinded, placebo-
`controlled study. Study 1218.15 was conducted at 43 sites in 7 countries outside the
`United States, in male and female subjects between 18 and 80 years of ago with type 2
`diabetes with insufficient glycaemic control. A total of 389 subjects were randomized in a
`2:1 fashion to linagliptin plus pioglitazone or placebo plus pioglitazone. Randomization
`was stratified by HbA1c value at the beginning of the placebo run-in period (< 8.5% or ≥
`8.5%) and the prior use of anti-diabetic drugs (none, monotherapy, combination therapy).
`Study 1218.15 was powered to provide 97% or greater power to detect a mean difference
`of 0.7% between linagliptin and placebo in HbA1c change from baseline to week 24.
`
`Study 1218.16 was a phase 3 multicenter, randomized, double-blinded, placebo-
`controlled study. Study 1218.16 was conducted at 66 sites in 11 countries outside the
`United States, in male and female subjects between 18 and 80 years of ago with type 2
`diabetes with insufficient glycaemic control (either drug naïve or despite with one oral
`anti-diabetic agent). A total of 503 subjects were randomized in a 2:1 fashion to
`linagliptin or placebo. Randomization was stratified by HbA1c value at the beginning of
`the placebo run-in period (< 8.5% or ≥ 8.5%) and the prior use of anti-diabetic drugs
`(none or monotherapy). Study 1218.16 was powered to provide 95% or greater power to
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`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 10 of 48
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`detect a mean difference of 0.7% between linagliptin and placebo in HbA1c change from
`baseline to week 24.
`
`Study 1218.17 was a phase 3 multicenter, randomized, double-blinded, placebo-
`controlled study. Study 1218.17 was conducted at 82 sites in 10 countries including the
`United States, in male and female subjects between 18 and 80 years of ago with type 2
`diabetes with insufficient glycaemic control despite therapy with metformin. A total of
`701 subjects were randomized in a 3:1 fashion to linagliptin or placebo in addition to
`ongoing background metformin therapy. Randomization was stratified by HbA1c value at
`the beginning of the placebo run-in period (< 8.5% or ≥ 8.5%) and the prior use of anti-
`diabetic drugs (metformin monotherapy or combination therapy). Study 1218.17 was
`powered to provide 95% or greater power to detect a mean difference of 0.7% between
`linagliptin and placebo in HbA1c change from baseline to week 24.
`
`
`Study 1218.18 was a Phase 3 multicenter, randomized, double-blinded, placebo-
`controlled study. Study 1218.18 was conducted at 100 sites in 11 countries outside the
`United States, in male and female subjects between 18 and 80 years of age with type 2
`diabetes with insufficient glycaemic control despite therapy with combination of
`metformin and sulphonylurea. A total of 1058 subjects were randomized in a 3:1 fashion
`to linagliptin or placebo. Randomization was stratified by the HbA1c value at the
`beginning of the placebo run-in period (<8.5% or ≥8.5%). Study 1218.18 was powered
`to provide 99% or greater power to detect a mean difference of 0.7% between linagliptin
`and placebo in HbA1c change from baseline to week 24.
`
`Study 1218.23 was a Phase 3 multicenter, randomized, double-blinded, placebo-
`controlled/active-controlled study. Study 1218.23 was conducted at 48 sites in Japan, in
`male and female Japanese subjects between 20 and 80 years of age with type 2 diabetes
`with insufficient glycaemic control despite being treated with diet and/or exercise only or
`with oral anti-diabetic drugs. A total of 561 subjects were randomized in a 1:2:2:2
`fashion to one of the following four treatment groups: placebo, linagliptin 5 mg,
`linagliptin 10 mg, and voglibose (two linagliptin does groups were combined in the meta-
`analysis). A dynamic allocation method was used to achieve homogeneity in the
`following three allocation factors across the four treatment groups: HbA1c value at the
`beginning of the placebo run-in period (<8.5% or ≥8.5%), number of previously used
`anti-diabetic drugs (0, 1, or 2), and gender (male or female). Study 1218.23 was powered
`to provide 90% or greater power to detect a mean difference of 0.5% between linagliptin
`and placebo in HbA1c change from baseline to week 12, and 90% or greater power to
`detect a mean difference of 0.45% between linagliptin and voglibose in HbA1c change
`from baseline to week 26.
`
`Study 1218.35 was a Phase 3 multicenter, randomized, double-blinded, placebo-
`controlled study. Study 1218.35 was conducted at 45 sites in 7 countries including the
`United States, in male and female subjects between 18 and 80 years of age with type 2
`diabetes with insufficient glycaemic control despite therapy with a sulfonylurea drug. A
`total of 245 subjects were randomized in a 2:1 fashion to linagliptin or placebo.
`Randomization was stratified by the HbA1c value at the beginning of the placebo run-in
`
`Reference ID: 2918087
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`NDA 201-280 (Tardjenta) Page 11 of 48
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`period (<8.5% or ≥8.5%) and the prior use of anti-diabetic drugs (sulfonylurea
`monotherapy or combination therapy). Study 1218.35 was powered to provide 90% or
`greater power to detect a mean difference of 0.7% between linagliptin and placebo in
`HbA1c change from baseline to week 18.
`
`Study 1218.50 was a Phase 3 multicenter, randomized, double-blinded, placebo-
`controlled/active-controlled study. Study 1218.50 was conducted at 53 sites in 7 countries
`including the United States, in male and female subjects between 18 and 80 years of age
`with type 2 diabetes with insufficient glycaemic control for whom metformin therapy was
`inappropriate (into