CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`209091Orig1s000
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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
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`S T A T I S T I C A L R E V I E W A N D E VA L U A T I O N
`CLINICAL STUDIES
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`NDA/BLA #:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`NDA 209091
`Saxagliptin/Dapagliflozin Fixed-Dose Combination (5 mg/10 mg)
`Type 2 diabetes mellitus
`AstraZeneca Pharmaceuticals
`Stamp: 4/27/2016
`Due date 23/01/2016
`
`Standard
`Review Priority:
`
`
`II
`Biometrics Division:
`Anna Kettermann, Dipl. Math, MA
`Statistical Reviewer:
`Concurring Reviewers: Mark Rothmann, PhD, Team leader
`
`
`Metabolism and Endocrinology Products
`Medical Division:
`Frank Pucino, Pharm. D, Medical reviewer
`Clinical Team:
`William Chong, MD, Clinical team leader
`Abolade Adeolu
`Project Manager:
`
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`Keywords: Missing data, subgroup analyses, regional differences, sensitivity analyses
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`Reference ID: 4036707
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`Table of Contents
`1 EXECUTIVE SUMMARY ................................................................................................................................. 5
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`2
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`3
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`INTRODUCTION ............................................................................................................................................... 7
`2.1
`OVERVIEW ...................................................................................................................................................... 7
`2.1.1
`Indication ............................................................................................................................................... 7
`2.1.2
`History of Drug Developement .............................................................................................................. 7
`2.1.3
`Specific Studies reviewed ....................................................................................................................... 7
`2.2
`DATA SOURCES .............................................................................................................................................. 8
`STATISTICAL EVALUATION ........................................................................................................................ 9
`3.1
`DATA AND ANALYSIS QUALITY ..................................................................................................................... 9
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................ 9
`3.2.1
`Study Design and Endpoints .................................................................................................................. 9
`3.2.2
`Statistical Methodologies ..................................................................................................................... 11
`3.2.3
`Patient Disposition, Demographic and Baseline Characteristics........................................................ 13
`3.2.4
`Results and Conclusions ...................................................................................................................... 17
`3.3
`EVALUATION OF SAFETY .............................................................................................................................. 22
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ............................................................................. 22
`4.1
`SEX, RACE, AGE, AND GEOGRAPHIC REGION ............................................................................................... 22
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS .................................................................................................. 24
`SUMMARY AND CONCLUSIONS ................................................................................................................ 27
`5.1
`STATISTICAL ISSUES ..................................................................................................................................... 27
`5.2
`COLLECTIVE EVIDENCE ................................................................................................................................ 28
`5.3
`CONCLUSIONS AND RECOMMENDATIONS ..................................................................................................... 28
`5.4
`LABELING RECOMMENDATIONS ................................................................................................................... 28
`APPENDICES ............................................................................................................................................................ 30
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`5
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`LIST OF TABLES
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`Table 1. List of all Phase 3 studies included in analysis ................................................................................................ 8
`Table 2. Sample size calculations ................................................................................................................................ 11
`Table 3. Demographic table ......................................................................................................................................... 14
`Table 4. Baseline data (Age and HbA1c) .................................................................................................................... 15
`Table 5. Missing data by study .................................................................................................................................... 16
`Table 6. Missing data by study and treatment group ................................................................................................... 17
`Table 7. Sponsor’s results (24 weeks)* ....................................................................................................................... 19
`Table 8. FDA results (24 weeks)** ............................................................................................................................. 20
`Table 9. Fasting plasma glucose and 2 hour post-prandial glucose* ........................................................................... 20
`Table 10. Subjects with HbA1c <7% at week 24 ........................................................................................................ 22
`Table 16. Subgroup analysis by sex ............................................................................................................................ 22
`Table 17. Subgroup analysis by race ........................................................................................................................... 23
`Table 18. Subgroup analysis by age ............................................................................................................................ 23
`Table 19. Subgroup analysis by region ........................................................................................................................ 24
`Table 20. Subgroup analysis by baseliene HbA1c ....................................................................................................... 26
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`LIST OF FIGURES
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`Figure 1. Design of study CV181168 ............................................................................................................................ 9
`Figure 2. Design of Study MB102129 ......................................................................................................................... 10
`Figure 3. Design of study CV181169 .......................................................................................................................... 10
`Figure 4. Longitudinal changes in HbA1c (MMRM analysis) .................................................................................... 17
`Figure 5. Study CV181168: Longitudinal changes based on completion status .......................................................... 18
`Figure 6. Study CV181169: Longitudinal changes based on completion status .......................................................... 18
`Figure 7. MB102129: Longitudinal changes based on completion status ................................................................... 19
`Figure 8. Longitudinal changes HbA1c and FPG Study CV181169 ........................................................................... 21
`Figure 9. Longitudinal changes HbA1c and FPG Study CV181168 ........................................................................... 21
`Figure 10. Follow-up time: comparison of cohort with and without data after recue therapy ..................................... 30
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`Reference ID: 4036707
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`1 EXECUTIVE SUNIMARY
`
`AstraZeneca submitted a new NBA for a fixed dose combination (FDC) tablet of saxagliptin (5
`mg) and dapagliflozin (10 mg). Both saxagliptin (saxa) and dapagliflozin (dapa) were previously
`approved as antihyperglycemic agents. Saxa-dapa was developed under IND 118840.
`
`The goal of this submission was to examine effects of adding saxagliptin (saxa) to treatment of
`subjects with Type 2 diabetes (T2DM) who require additional glycemic control and currently on
`maximum recommended dose of dapagliflozin (10 mg) and metformin. The proposed FDC is
`indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM
`00(4)
`
`The submission is comprised of three Phase 3 trials (CV181168 CV181169, and NIB102129).
`Two of the studies (CV181 169 and MB102129) were add-on studies (saxa was added to dapa in
`study CV181168, and dapa was added to saxa in study MB102129). The third study, trial
`CV181169, introduced both saxa and dapa concomitantly. All studies had a 24-week short-term
`efficacy period. Two add-on studies had an additional 28-week extension. Efficacy was
`evaluated only for the first 24—week period.
`Because saxa-dapa FDC is only indicated to subjects who are already on maximum dose of dapa,
`the sponsor is seeking labeling only for the trial CV181168.
`
`My recommendations:
`
`M"
`Update the text of section 14 of the label
`Instead, I would suggest providing the intent-to-treat (de facto) estimands, which consider the
`actual measurements of subjects regardless of adherence to treatment or use of subsequent
`therapy. A pattem-mixture imputation approach could be used to obtain those estirnands.
`
`I recommend including information on dropout rates by treatment group on the product label.
`Also, I suggest including information on rates of retrieved dropouts.
`
`(I!) (4)
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`(I'M
`I recommend that the paragraph titled
`be renamed “Proportion of patients known to have achieved HbAlc<7%” in order
`to make it clear that there were no formal testing of this hypothesis, i.e. there was no Type I error
`adjustment in calculation of these results.
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`Statistical Issues and findings
`
`1.
`
`Substantial evidence of efficacy. In all Phase 3 studies, treatment with the saxa-dapa
`combination resulted in larger HbAlc reduction at week 24 than saxa or dapa alone when
`given in combination with metformin. Primary analysis results were consistent between
`sponsor’s analyses and FDA analyses. Based on the FDA analysis examining data
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`obtained within the first 24 weeks from randomization, the HbA1c reduction in the saxa-
`dapa arm was larger than in the dapa arm without addition of saxa (0.3%, CI (0.2, 0.5) in
`study CV181168 and 0.3% CI(0.1, 0.5) in study CV181169). Similarly, saxa-dapa
`presented a larger reduction in HbA1c when it was compared to saxa without addition of
`dapa (0.5%, CI (0.3, 0.7) in study CV181169 and 0.6%, CI (0.4, 0.8) in study
`MB102129).
`
`
`Handling dropouts. The sponsor’s analysis did not take into account data of subjects
`who were rescued or dropped out prior to the end of the short-term efficacy period, thus
`evaluating only subjects who were able to tolerate the drug.
`
`
`Missing data. The amount of missing data ranged between 5 and 10% across all
`studies. Study CV181169 had the largest amount of missing data, with the largest fraction
`of subject dropout in the dapa arm (12.3%). The lowest amount of missing data was
`observed among subjects in study CV181168, with the dapa arm having the lowest loss
`of subjects (3.7%). The largest fraction of subjects who discontinued the drug but had an
`HbA1c measurement at endpoint was observed in study MB102129 (7.5%, most of those
`subjects were from the saxa arm).
`
`
`Hierarchical testing for secondary endpoints. In studies where dapa was compared
`to saxa-dapa (studies CV181169 and CV181168), the results of change in PPG (the first
`endpoint that was pre-specified in the hierarchy) were not significant. Therefore the
`testing for the secondary endpoints was stopped after the first comparison in those
`studies. In contrast, both, PPG and FPG comparisons yielded favorable results for saxa-
`dapa when the combination was compared to saxa without dapa.
`
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`Subgroup analyses. The effects of saxa-dapa were similar across all subgroups.
`Only when data were examined by region, a comparison between the saxa-dapa and dapa
`arms showed that the effect went in the opposite direction, favoring dapa, in North
`America. (The reduction in the dapa arm was larger than in the saxa-dapa arm in study
`CV181169 0.03% CI (-0.26, 0.32), while in study CV181168, the outcomes for the saxa-
`dapa arm showed lower efficacy in North America than in any other region when
`compared to dapa).
`
`
`Longitudinal changes in FPG. Of note, the longitudinal changes in FPG had
`different patterns than changes in HbA1c, showing less difference in outcomes when
`treatment with saxa-dapa and dapa without saxa component were compared (studies
`CV181168 and CV181169). This leads me to conclude that the effect of saxa-dapa on all
`glucose parameters is not uniform. This outcome could be a result of larger variability of
`FPG as a biomarker.
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`6.
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`2
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`INTRODUCTION
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`2.1 Overview
`
`A brief description of the drug indication and history of the submission is presented below.
`
`2.1.1 Indication
`
`The goal of this submission was to examine effects of adding saxagliptin (saxa) to treatment of
`subjects with Type 2 diabetes (T2DM) who require additional glycemic control and currently on
`maximum recommended dose of dapagliflozin (10 mg) and metformin. The proposed FDC is
`indicated as an adjunct to diet and exercise to improve glycemic coggol in adults with T2DM
`
`Saxagliptin is a dipetptidyl peptidase—4 (DPP4) inhibitor approved in 2009, available in 2.5 mg
`and 5 mg tablets. Dapagliflozin is a sodium-glucose cotransporter 2 (SGLTZ) inhibitor approved
`in 2014, available in 5 mg and 10 mg tablets. While dapagliflozin is approved for monotherapy,
`it is typically prescribed as a second—line treatment in combination with metfonnin and/or other
`antihyperglycemic agents. Both drugs are indicated as an adjunct to diet and exercise to improve
`glycemic control in adults with T2DM.
`
`2.1.2 History of Drug Developement
`
`FDC tablets
`
`(I'm) the sponsor submitted an NDA
`
`(am) for the saxagliptin/dapagliflozin
`(m4)
`
`Both saxagliptin (saxa) and dapagliflozin (dapa) were previously approved as
`antihyperglycemic agents. Saxa—dapa was developed under IND 118840. The NDA was based on
`the eflicacy and safety results of study CV181169 where saxagliptin and dapagliflozin were
`added concomitantly (dual add-on) in T2DM patients who had inadequate glycemic control on
`metfonnin alone. The application received a Complete Response Letter (CRL) on 15 October
`2015, in which FDA requested submission of additional clinical data
`“(4)
`
`Following type A meeting with the Agency, Astra Zeneca submitted a new NDA 209091 on
`4/27/2016 for a fixed dose combination (FDC) tablet of saxagliptin (5 mg) and dapagliflozin (10
`mg).
`
`2.1.3 Specific Studies reviewed
`
`The submission is comprised of three Phase 3 trials. Two of the studies (CV181169 and
`lVlB102129) were add-on studies (saxa was added to dapa in study CV181168, and dapa was
`added to saxa in study MB102129). The third study, trial CV181169, introduced both saxa and
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`dapa concomitantly. All studies had a 24-week short-term efficacy period. Two add-on studies
`had an additional 28-week extension. Efficacy was evaluated only for the first 24-week period.
`Because saxa-dapa FDC is only indicated to subjects who are already on maximum dose of dapa
`(10 mg), the sponsor is seeking labeling only for the trial CV181168.
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`Table 1. List of all Phase 3 studies included in anal sis
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`Phase and
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`Design
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`Treatment
`Period
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`# of Subjects per
`Arm
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`Completed
`24 weeks ("/0)
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`ST: 24 weeks (efficacy)
`LT: 28 weeks (extension)
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`Saxa+dapa 153
`Pla+dapa 162
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`Saxa+dapa
`7.2
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`Pla+dapa
`3.7
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`CV181168*
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`Randomized,
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`double-blind,
`placebo-
`controlled,
`parallel
`gl-011pa
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`sequential
`add-on
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`CV181169
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`Randomized,
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`ST: 24 weeks (efficacy)
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`double-blind,
`active-
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`controlled,
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`parallel
`group,
`concomitant
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`add-on
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`Saxa+dapa 179
`Saxa
`l 76
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`Dapa
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`179
`
`NIB102129
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`Randomized,
`double-
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`ST: 24 weeks (efficacy)
`LT: 28 weeks (extension)
`
`Saxa+dapa 160
`Pla+saxa
`160
`
`Saxa+dapa
`5.5
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`Saxa
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`8.5
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`Dapa
`10.6
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`Saxa+dapa
`7.5
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`Pla+saxa
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`4.4
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`blind,
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`placebo-
`controlled,
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`parallel
`group,
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`sequential
`add-on
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`* Study included in the proposed label
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`2.2 Data Sources
`
`This submission is in electronic common technical document (eCTD) format. The submission is
`archived at the following link: \\CDSESUB l\evsprod\NDA20909l\20909l .enx
`
`Study datasets were provided as SAS XPORT transpofl files. The analysis datasets were joinable
`by unique identifier (SUBJID). The datasets were in good organization. Define.pdf file was clear
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`enough. My analysis on the primary and secondary efficacy endpoints gives approximately the
`same results as those reported in the clinical study report (CSR).
`
` I
`
` derived from the submitted datasets all of the results presented in this review. I created all
`tables and figures in this review unless otherwise noted.
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` STATISTICAL EVALUATION
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`3.1 Data and Analysis Quality
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`The submission quality was found to be reasonable.
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`3.2 Evaluation of Efficacy
`3.2.1 Study Design and Endpoints
`
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`The submission consisted of three randomized, double-blind, placebo-controlled studies with
`parallel-group design. All three studies had a 24-week short-term efficacy period. Two add-on
`studies had an additional 28-week extension. Efficacy was evaluated only for the first 24-week
`period.
`A schematic description of all three studies is presented below.
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`Figure 1. Design of study CV181168
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`Source: Clinical overview p.26
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`Figure 2. Design of Study MB102129
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`Source: Clinical Study Report p. 3
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`Figure 3. Design of study CV181169
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`Source: Clinical Study report p. 3
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`All participants in all three studies were required to be on a stable dose of metformin prior to
`randomization. During lead-in period all subjects received open-label metformin. In Studies
`CV181168 and MB102129, saxagliptin and/or dapagliflozin were coadministered with
`metformin immediate release (IR). In Study CV181169, saxagliptin and/or dapagliflozin were
`coadministered with metformin extended release (XR). Both, metformin IR and XR were dosed
`at the upper end of the dose-response for metformin.
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`During all trials, study treatment and metformin were not to be titrated during the double-blind
`treatment period. The study drug was administered orally once daily.
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`Primary efficacy endpoint:
`Change in HbAlc from baseline to week 24
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`Secondary efficacy endpoints:
`1. Change in 2-hour post-prandial glucose (PPG) during a liquid meal test from baseline
`to week 24
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`2. Mean change from baseline to each time point in HbAlc and in fasting plasma
`glucose (FPG).
`3. Percent of subjects achieving a therapeutic glycemic response, defined as HbAlc <
`7.0%, and time to glycemic rescue, or discontinuation, due to lack of efficacy, fiom
`baseline to each time point.
`
`Control of type—I error:
`The study-wise type-I error was controlled at 5% using a hierarchical testing strategy. Both two-
`sided p-values from the comparison of the monotherapies to Saxa-Dapa needed to be less than
`0.05 to move to the subsequent level in the testing hierarchy.
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`Sample size calculations:
`In all three studies, the sponsor’s calculations of sample size were based on testing of the
`primary study endpoint, which was the change from baseline in HbAlc at the end of the 24-
`week, short—term double-blind, treatment period. All sample size calculations were made with
`the goal of detecting a difference in mean HbAlc change of 0.4% between Saxa-Dapa and each
`of the monotherapies assuming 90% power and a standard deviation of at least of 1.0%. The
`study-specific sample sizes are presented in the Table 2 located below.
`
`Table 2. Sample size calculations
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`Study
`
`CVl81168
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`CV181169 MB102129
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`1.0%
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`Total number of subjects
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`Number of subjects per arm
`Power
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`Difference in HbAlc change
`Standard deviation
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`240
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`140
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`280
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`140
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`516
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`172
`90%
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`0.4%
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`3.2.2 Statistical Methodologies
`
`Sponsor’s approach:
`Data analysis: A longitudinal repeated measures analysis was used to estimate the change in
`HbAlc and FPG fiom baseline; the model included the categorical fixed effects of treatment,
`week, and treatment—by—week interaction as well as the continuous fixed covariates of baseline
`measurement and baseline measurement-by—week interaction. Rescue was added as an additional
`categorical fixed effect in this mixed model when the analysis was performed on data regardless
`of rescue.
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`Primary analysis population and analysis dataset: The primary analysis population consisted
`of all randomized subjects that received at least one dose of study medication during the double-
`blind treatment period. HbA1c data obtained after discontinuation of protocol treatment were
`excluded from the primary analysis.
`
`FDA approach:
`Primary analysis and population: Because all post-discontinuation data points were excluded
`from the analysis, the sponsor’s analysis examines the effect of week 24 HbA1c change under
`the assumption that no subject experienced rescue during the trial. I do not believe that in clinical
`practice none of the subjects for whom the drug is intended will need rescue. Thus, the outcomes
`based on this assumption might not be realistic. Also, subjects who discontinued treatment would
`not have the same outcomes as subjects who completed the entire treatment period. Analysis that
`excludes all post-discontinuation data will not represent all subjects who participated in the
`study. Therefore my analysis will include data regardless of adherence, i.e. all available data
`points collected after rescue or discontinuation will be included in the analysis. In my view, this
`approach more appropriately describes real world outcomes.
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`Also, in my analysis, I implemented a multiple imputation approach that imputed data for
`subjects who did not have HbA1c endpoint at week 24.
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`Imputation approach (retrieved dropouts ANCOVA):
`1. First, 500 copies of the dataset were generated.
`2. The imputation for subjects who did not have endpoint observation was performed using
`data from subjects who discontinued, but had post-rescue data (retrieved dropouts).
`Imputations were stratified by treatment group and baseline HbA1c.
`3. For each dataset separately, the change in HbA1c at week 24 was analyzed using
`ANCOVA model. Each ANCOVA model contained baseline HbA1c and treatment group
`as covariates.
`4. Results from an ANCOVA model fit to the imputed datasets were analyzed and
`combined using Rubin’s method. Treatment effect estimates and limits from the 95%
`confidence interval (CI) were retained.
`
`
`Sensitivity analyses:
`Alternative imputation approach: Jump to Reference (J2R)
`A pattern mixture model was used mimicking an ITT scenario where subjects who withdrew
`from the saxa-dapa group were assumed to be switched to the comparator treatment after
`withdrawal, while subjects treated with the comparator were assumed to remain on their assigned
`treatment throughout the trial. Subjects who withdrew from the saxa-dapa group were assumed
`to be switched to the comparator used in the trial.
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`Alternative imputation approach: Copy Reference (CR)
`Similar to Jump to Reference approach, a pattern mixture model was used. The only difference
`to Jump to Reference is that subjects who withdrew from the saxa-dapa group were assumed to
`respond as if they had been treated with the comparator for the entire trial, while subjects treated
`with the comparator were assumed to remain on their assigned treatment throughout the trial.
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`Tipping point analysis
`To further evaluate the robustness of the conclusions, a tipping point analysis of the approach
`assumed “copy reference” was performed. As described in the “copy reference” methodology
`above, in this analysis, subjects who withdrew from the saxa-dapa arm were assumed to have
`received a treatment inferior to the comparator. A ‘penalty’ was added to the endpoint HbA1c
`values that were imputed for the subjects who dropped out. The extent of ‘penalty’ was gradually
`increased to evaluate at which point saxa-dapa was no longer statistically significantly better
`than a comparator. This penalty value, also known as the tipping point, corresponded to a
`hypothetical degree of efficacy deterioration in withdrawn subjects needed to shift the treatment
`effect of saxa-dapa from being statistically significantly better than the comparator to a non-
`statistically significant effect.
`
`MMRM analysis
`Similar to the sponsor, a longitudinal repeated measures analysis was used to estimate the change
`in HbA1c from baseline until week 24; the model included the categorical fixed effects of
`treatment, week, and treatment-by-week interaction as well as the continuous fixed covariates of
`baseline measurement and baseline measurement-by-week interaction. All analyses were
`performed using all data points obtained prior to and after the rescue/discontinuation.
`
`
`3.2.3 Patient Disposition, Demographic and Baseline Characteristics
`Demographics and baseline characteristics are presented in Table 3 and in
`Table 4. Overall, demographic characteristics were similar (Table 3). Most of the subjects were
`from North America (with exception of study mb102129). Subjects from study CV18168 had
`slightly lower baseline HbA1c then subjects in all other studies. Baseline values were consistent
`across arms within each study.
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`Table 3. Demographic table
`
`Trial
`arm
`
`PLA +
`DAPA +
`MET
`
`SAXA +
`DAPA +
`MET
`
`SAXA+
`MET
`
`AMERICAN
`INDIAN/HAWAIIA
`N/ALASKA
`NATIVE
`ASIAN
`BLACK/AFRICAN
`ARTERICAN
`OTHER
`WHITE
`AMERICAN
`INDIAN/ALASKA
`NATIVE
`ASIAN
`BLACK/AFRICAN
`AMERICAN
`OTHER
`WHITE
`ALERICAN
`lNDIAN/HAWAIIA
`N/ALASKA
`NATIVE
`ASIAN
`BLACK/AFRICAN
`AMERICAN
`OTHER
`WHITE
`
`1.23
`
`4.94
`5.56
`
`1.23
`87.04
`
`3.27
`7.19
`
`0.65
`88.89
`
`1
`136
`
`PLA +
`DAPA +
`MET
`
`hiale
`
`Female
`
`76
`
`86
`
`46.91
`
`53.09
`
`Number of
`subjects
`
`Percent
`
`Number of
`subjects
`
`Percent
`
`Number of
`subjects
`
`Percent
`
`18
`
`10
`16
`
`4
`131
`
`19
`
`12
`22
`
`120
`18
`
`11
`22
`
`121
`
`89
`
`90
`
`10.06
`
`5.59
`8.94
`
`2.23
`73.18
`
`10.56
`
`6.67
`12.22
`
`3.89
`66.67
`10.23
`
`6.25
`12.50
`
`2.27
`68.75
`
`49.72
`
`50.28
`
`0.63
`5.00
`
`0.63
`93.75
`1.26
`
`0.63
`6.25
`
`1.88
`
`10
`
`147
`
`73
`
`80
`
`55
`21
`86
`
`55
`20
`78
`
`47.71
`
`52.29
`
`33.95
`12.96
`53.09
`
`35.95
`13.07
`50.98
`
`SAXA +
`DAPA +
`MET
`
`SAXA+
`MET
`
`PLA +
`DAPA +
`MET
`
`SAXA 1-
`DAPA +
`MET
`
`SAXA+
`MET
`
`Male
`
`Female
`
`Male
`
`Female
`
`EUROPE
`LATIN AMERICA
`NORTH
`AMERICA
`ASIA/PACIFIC
`
`EUROPE
`LATIN ALIERICA
`NORTH
`A.\iERICA
`ASIA/PACIFIC
`EUROPE
`LATIN AMERICA
`NORTH
`AVIERICA
`ASIA/PACIFIC
`
`85
`
`95
`
`94
`
`82
`
`38
`100
`
`888
`
`34
`
`99
`
`47.22
`
`52.78
`
`53.41
`
`46.59
`
`22.35
`21.23
`55.87
`
`0.56
`
`22.22
`22.22
`54.44
`
`1.11
`19.32
`22.73
`56.25
`
`1.7
`
`70
`
`90
`
`76
`
`84
`
`51
`54
`55
`
`63
`49
`48
`
`43.75
`
`56.25
`
`47.50
`
`52.50
`
`31.88
`33.75
`34.38
`
`39.38
`30.63
`30.00
`
`Reference ID: 4036707
`
`14
`
`

`

`Table 4. Baseline data (Age and HbAlc)
`Arm
`_\
`
`llinimum )Iaximum )Iean
`
`Std
`Dev
`
`C'oeff of
`Variation
`
`PLA +
`DAPA +
`MET
`
`Baseline Value
`
`Change from Baseline
`
`Length of follow-up
`(weeks)"
`
`Age
`Baseline Value
`
`
`
`Change from Baseline
`
`Length of follow-up
`(weel5)‘r
`
`Age
`Baseline Value
`
`Change from Baseline
`
`Length of follow—up
`(weeks)*
`
`Age At Consent Date
`Baseline Value
`
`Change fmm Baseline
`
`Length of follow-up
`(weelsr‘
`
`Age At Consent Date
`Baseline Value
`
`Change from Baseline
`
`Length of follow-up
`(weele‘
`
`Age At Consent Date
`Baseline Value
`
`Change from Baseline
`
`Length of follow-up
`(weel5)*
`
`Age At Consent Date
`Baseline Value
`
`Change from Baseline
`
`Length of follow-up
`(weeks)"
`
`
`
`Studycv181168
`
`Ox
`9_
`o_
`
`_c
`
`>0>
`
`5
`'5
`=H
`(0
`
`
`
`Studymb102129
`
`Reference ID: 4036707
`
`15
`
`

`

`Missing data
`
`Overall, the amount of missing data in all three trials was not very large (5-10%). Study
`CV181169 had the largest fraction of subjects who dropped out prior to their 24-week visit. In
`contrast, study CV181168 had the lowest dropout rate. The largest fraction of subjects who were
`put on rescue therapy and had HbAlc measurement at week 24 (retrieved dropouts) was
`observed in study MB102129 (7.5%). A graphical illustration of dropout and rescue patterns in
`each study is shown in the appendix (Figure 13).
`
`SAXA+DAPA
`
`DAPA
`
`SAXA
`
`Total
`
`
`
`6 (3.7%)
`7(4.3%)
`22 (12.3%)
`6(3.4%)
`
`Missing
`Retrieved
`
`CV181168
`
`CV181169
`
`M3102129
`
`16 (5.1%)
`10* (6.5%)
`11(3.5%)
`4 (2.6%)
`53(9.9%)
`l7(9.7%)
`l4(7.8%)
`31(5.8%)
`l7(9.7%)
`8(4.4%)
`Retrieved
`23(7.2%)
`11(6.9%)
`12(7.5%)
`Missing
`24(7.5%)
`22(13.8%)
`2(1.2%)
`Retrieved
`*Table 5.1-lp. 47 Clinical Study Report indicates that there were 11 subjects who dropped out, but the submitted dataset
`contained data on 143 (i.e. only 10 subjects were missing) subjects at week 24. The discrepancy could be due to the fact that
`sponsor excluded post-rescue dam fi'om the analysis.
`
`During my review I identified one study (CV181168) where an entire region (Latin America) did
`not have any dropouts or rescue during the 24-week efficacy period. All subjects from Latin
`America came from four study sites located in Mexico (study sites 0072, 0073, 0074, and 0075).
`
`The results presented in Table 6 are illustrating missing data patterns by treatment group and
`region. No robust conclusion on all those patterns could be made because the number of
`dropouts was small. Of note, the number of subjects who dropped out of the study was larger
`among study participants from North America. This pattern could be partially explained by the
`fact that the largest number of subjects came from North America, although study CV181169
`had disproportionally many dropouts among subjects fiom North America. Overall, study
`CV181169 had the largest amount of missing data.
`
`Reference ID: 4036707
`
`16
`
`

`

`Table 6. Missing data by study and treatment group
`
`PLA + DAPA
`
`Retrieved*
`
`Dropout" *
`
`CV181168
`
`CV181169
`
`PLA + SAXA
`
`MB]02129
`
`”A?“ SA“
`
`‘Subjects who discontinued protocol treatment and had a 24—week evaluation
`" Subjects who did not have an observation at week 24
`
`3.2.4 Results and Conclusions
`
`3.2.4.1 Graphical exploration
`
`An illustration of longitudinal changes of HbAlc by study is presented in Figure 4. Of note, the
`difference between saxa-dapa and its components becomes smaller after the short-term efficacy
`period is over. The reason of such a change could possibly be because of the discontinuation
`pattern during the safety part of the study.
`
`Figure 4. Longitudinal changes in HbAlc (MMRM analysis)
`
`cv181168 chnagein l-BA1c WITH Rescuedata
`3“?
`ST
`I
`LT
`(0
`|
`2 '
`.
`._v.
`§
`.
`N
`5
`I
`
`°
`
`510152025303540455055
`StudyWeek
`
`cv181169chmgein HBA1cWITHRm1edata
`3“
`ST
`gun
`5'
`‘_
`%
`no
`°
`
`681012141618202224
`Mme"
`I—l womFAQIEr I—l must
`% m
`
`mb102129 chnage in HBA1c wrrH Rescue data
`3..
`ST
`|
`LT
`
`< f
`
`.5")
`
`5’
`
`3 W00
`
`|
`l
`
`|
`
`510152025303540455055
`StudyWeek
`l—l MOMOET l—l PunsmmnEr
`
`17
`
`Reference ID: 4036707
`
`

`

`A simple graphical comparison of longitudinal HbAlc patterns based on study completion status
`(completers, dropouts, and subjects who were retrieved) is presented in
`Figure 5, Figure 6, and in Figure 7, suggesting that subjects who were retrieved had less
`reduction in HbAlc than subjects who stayed on protocol treatment. Also, in most of the cases,
`subjects who dropped out, i.e. did not have a 24-week evaluation, had HbAlc values aligned
`closer with values of retrieved subjects. An examination of these patterns sugg