Individual Study Table Referring
`to the Dossier
`
`(For National Authority Use
`Only)
`
`CV181039
`Final Clinical Study Report
`
`Saxagliptin
`BMS-4771 18
`
`Name of Sponsor/Company:
`Bl,iStO1_Myel_s Squibb
`Name of Finished Product:
`
`Name of Active Ingredient:
`Saxagliptin
`
`SYN OPSIS
`
`Final Short-Term Clinical Study Report for Study CV181039
`
`to
`TITLE OF STUDY: A Multicenter, Randomi7ed, Doul')le—P;lind, Active-Controlled, Phase 3 Trial
`Evaluate the Eflicacy and Safety of Saxagliptin in Combination with Metforrnin IR as Initial Therapy
`Compared to Saxagliptin Monotherapy and to Metformin IR Monotherapy in Subjects with Type 2
`Diabetes Who Have Inadequate Glyeemic Control
`
`196 investigators at 196 sites (46 in Russian Federation, 44 iii
`INVESTIGATORS/STUDY CENTERS:
`the United States, 19 in Argentina, 13 in India, 13 in Mexico, 12 in Germany,
`IO in the Ukraine, 8 in
`Brazil, 8 in Poland, 8 in the Philippines, 6 in Puerto Rico, 5 in Hungary, and 4 in Italy)
`PUBLICATIONS: None
`
`STUDY PERIOD:
`
`Study Initiation Date:
`
`30-May-2006
`
`CLINICAL PHASE:
`
`3
`
`Study Completion Date:
`
`27-Nov-2007
`
`OBJECTIVES:
`Primary Efficacy Objective - To compare, after 24 Weeks of oral administration of double-blind
`treatment, the change from baseline in hemoglobin AIC (AIC) achieved with each dose of saxagliptin +
`nictformin immediate release (IR) compared to saxagliptin + placebo and to mctformin IR + placebo in
`subjects with type 2 diabetes who have inadequate glycemic control defined as AIC 2 25% but 5 12%.
`
`Secondary Efficacy Objectives - To compa1‘e each dose of saxagliptin + inetfoirnin IR versus saxagliptin
`+ placebo and metformin IR + placebo after 24 weeks of oral adininistration of double—blind therapy for the
`following: 1) change from baseline in fasting plasma glucose (FPG), 2) proportion of subjects achieving a
`therapeutic glycemic response defined as AIC < 7.0%, 3) change from baseline in the AUC from 0 to 180
`minutes for postprandial glucose (PPG) response to a11 oral glucose tolerance test (OGTT), 4) proportion of
`subjects achieving a therapeutic glycemic response defined as AlC S 6.5%, and 5) proportion of subjects
`requiring rescue for failing to achieve pre-specified glycemie targets or discontinuing for lack of efficacy
`within the 24 week, short-Ierrn, double-blind treatment period.
`
`IR versus
`Other Efficacy Objectives - To compare/assess each dose of saxagliptin -l- metfomiirr
`saxagliptin + placebo and metformin IR -l- placebo for the following: I) differences in the change from
`baseline to \7\/eek l2 in FPG, 2) differences in the change from baseline to Week 24 for the following: a)
`AUC from 0 to 180 minutes for postprandial insulin, postprandial glucagon and postprandial C-peptide
`response to an OGTT. b) beta cell function (as measured by Homeostasis Model Assessment, HOMA-2B),
`C)
`insulin resistance (as measured by HOMA—2 IR), d’) fasting glucagon, fasting insulin and fasting
`C.-peptide, e) glucose, C-peptide, insulin, and glueagon concentrations at 0-, 30- 60, 120- and 180 minutes
`during an OGTT, 1) excursion profiles for glucose, C-peptide,
`insulin, and glucagon concentrations
`(defined as the difference between 0 minutes and 30, 60, l20 and lS0 minute postprandial values) after an
`OGTT, g) insulin sensitivity and B-cell function derived from measurements of insulin, C-peptide and
`
`Approved V1.0
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`930027411 1.0
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`I
`
`Hyian V. !stra!eneca
`
`IPR2015-01340
`
`AstraZeneca Exhibit 2199
`Mylan v. AstraZeneca
`IPR2015-01340
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`Page 1 of 10
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`

`
`Saxagliptin
`BMS-4771 18
`
`CV1 81039
`Final Clinical Study Report
`
`glucose during the OGTT, h) body mass index (BMI), waist circumference, and total body Weight, i) the
`proportion of subjects achieving a glyeemie response for each of tl1e following categories: AlC S 8.0%.
`reduction in AIC 2 0.5%, reduction in AIC 2 0.7%, FPG < 110 mg/dL (6.1 mmol/L), FPG < 126 mg/dL
`(7.0 mmol/L), 120-minute PPG < 140 mg/dL (7.8 mmol/L), 120-minute PPG < 200 mg/dL (11.1 mmol/L),
`(j) percent change from baseline in fasting lipids:
`total cholesterol
`(total—C),
`low density lipoprotein
`cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), and free fatty acids
`(FFA), (k) change from baseline in metabolic surrogate markers (hs-CRP, PAI-l, and fibrinogen) and
`interleukin-6 (IL-6) and
`proportion of subjects requiring rescue for failing to achieve pre-specified
`glycemic targets or discontinuing for lack of efficacy at Weeks 4, 6, S, 12, 16, 20 and 24.
`
`Safety Objective - To assess the safety and tolerability of each dose of saxagliptin + mctformin IR,
`saxagliptin + placebo and metformin IR + placebo when administered for up to 24 weeks of short—term
`double—blind therapy.
`
`double-blind,
`group,
`4-arm, parallel
`randomized,
`3,
`a Phase
`l\1F.TI-IODOLOGY: This was
`active-controlled, multi-center study in din g naive subects with inadequate glycemic control (AIC 28.0%
`and 312.0%). Following screening evaluations, subjects who met eligibility criteria were enrolled in a
`1-week, single—blind. dietary and exercise placebo lead—in period. Subjects meeting the randomization
`criteria were randomized (l :
`l :l :1) in a double—blind fashion to either saxagliptin 10 mg plus metformin [R
`500 mg (Saxa lOn1g 1 Met), saxagliptin 5 mg plus metformin IR 500 mg (Saxa 5mg|Met). saxagliptin
`10mg plus placebo {Saxa 10mg), or metformin IR 500 mg plus placebo (Met). At Week I, subjects
`receiving metformin as monotherapy or in combination with saxagliptin were to be titrated, as tolerated,
`from metformin 500 mg/d to 1000 mg/d in divided doses. At \Veeks 2, 3, 4, and 5, subjects were to be
`titrated, as tolerated, in increments of 500 mg up to a maximum of 2000 mg/d in divided doses if mean
`fasting plasma glucose (MFPG) > MO mg/dL (6.1 mmol/L) or mean fasting whole blood glucose
`(MFWBG) > 104 mg/dl_. (5.8 mmol/L). Subjects who met glycemic rescue criteria during the 24-week,
`short—term period were eligible to enter the long-term (12 months) period where they received open—label
`pioglitazone added to their blinded study medication. Subjects who completed all visits during the 24-
`week, short—term period and did not meet glyeemic rescue criteria were eligible to enter the long-term
`period Where they received the same treatment as they received during the short—term period. The long-term
`extension period is ongoing.
`
`NURIBER OF SUBJECTS [Planned and Analyzed): Planned (enrolled) 1470; Enrolled (_ signed study
`specific informed consent) 2936; Entered lead-in period 1394; Randomized 1309; Treated 1306; Total
`treated with saxagliptin 978. A total 01°99] subjects completed the short—term period. Of the 3 I 5 subjects
`who did not complete short—term treatment, 137 were rescued and went into the long-term phase of the
`study.
`
`DIAGNOSIS AND l\rIAIN CRITERIA FOR INCLUSION:
`
`Subjects with a diagnosis oftype 2 diabetes mellitus
`0
`0 AlC 2 8% but 3 12% obtained at the screening visit
`0
`Fasting C-peptide concentration 2 l .0 ng/ml
`0
`Subjects were to be ding l‘lB.1'\'€. Ding naive subjects were defined as subjects who have never received
`medical treatment for diabetes (insulin and/or oral hypoglycemic agents) or have received medical
`treatment for diabetes for less than a total of 1 month since original diagnosis. In addition, subjects
`should not have received any antihyperglyeemie therapy for more than 3 consecutive days or a total of
`7 non-consecutive days during the 8 weeks prior to screening. The exceptions were for women who
`have received treat.ment for gestational diabetes during their pregnancy and were no longer receiving
`therapy or subjects who during a hospitalization received a short course of insulin treatment.
`
`.
`
`BMI s 40 kg/m2
`
`Approve.-CI. V1.0
`
`930027411 1.0
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`Page 2 of 10
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`
`Saxagliptin
`BMS-4771 18
`
`CV181039
`Final Clinical Study Report
`
`TEST PRODUCT, DOSE AND RIODE OF ADIVIINISTRATION, DURATION OF TREATl\/IENT,
`BATCH NUMBERS: Saxagliptin (BMS-477118)
`tablets used during the 24-week, double-blind,
`short-term period are shown in the table below. Subjects were instructed to take 1 tablet daily prior to the
`morning n1eal.
`
`Product
`
`Potency
`
`Appearance
`
`Batch Numbers
`
`Saxagliptin
`
`5 mg as the free base
`
`Plain, yellow, biconvex,
`round, film coated tablet
`
`6Hl7796, 6Cl5675, 6B 19549
`
`Saxagliptin
`
`10 mg as the free base
`
`Plain» Yellow» biC0nVBX~
`round, film coated tablet
`
`5LO8927, 6C15678, 6E12062
`
`REFERENCE THERAPY, DOSE AND MODE OF ADl\IINISTRATION, DURATION OF
`TREATIVIENT, BATCH NUMBERS: lflatching placebo tablets for saxagliptin and open-label metforinin
`tablets used during the 24-week, double-blind, short-term period are shovm in the following table. Subjects
`in the Met group Were instructed to take 1
`tablet of saxagliptin placebo daily prior to the morning meal.
`Subjects in the Saxa |0mg group were instructed to take 1
`tablet ofmetformin placebo daily prior to the
`morning meal. If at the Week 1, 2, 3, 4 or 5 Visit, a subject in the Saxa 5mg l Met. Saxa 10mg I Met and
`blet groups met the criteria to initiate blinded metforinin titration, titration was to occur as follows. Note
`that subjects in the 3 groups who received metformin had to titrate in a blinded fashion. Subjects in the
`Saxa 10 mg group received dummy titration.
`
`Initial titration: Q tablet(s) daily with the morning meal, 1 tablet daily with the evening meal.
`
`Second titration: 1 tablet daily with the morning meal, 1 tablet daily with the evening meal.
`
`Third titration: 1 tablet daily with the morning meal, ; tablets daily with the evening meal.
`
`Product
`
`Saxagliptin Placebo
`
`Metformin _
`l-lydrochlorl de
`
`Potency
`
`N/A
`
`500 mg
`
`Appearance
`
`Batch Numbers
`
`Plain, yellow, biconvex,
`round, film coated tablet
`
`61513898, 6131389‘),
`6Hl7797
`
`Wlllte to off—white, round,
`i'Ilm—coated tablet
`
`(LA172795 6D] 69565
`6D1-7286: 6H16141
`
`l\/letl"o1‘mir1 Placebo
`
`N/A
`
`White to 0fl"—Wl]ite, round,
`film—coated tablet
`
`61312609: 5121037
`
`Subjects meeting the criteria for rescue during the 24—Week, short—term period were eligible to enter the
`long—term (12 months) period Where they received open—label pioglitazone added to their blinded study
`medication. Subjects were instructed to take pioglitazone daily prior to the morning meal.
`
`Product
`
`Pioglitazone HCl
`(US sourced product)
`
`Pioglitazone l—lCl
`(UK sourced product)
`
`Potency
`
`15 mg
`
`15 mg
`
`Appearance
`
`Batch Numbers
`
`White to off—white, round,
`flat, non-scored tablet
`
`White to ofi‘-white, round,
`flat tablet
`
`71326486 7G22196
`
`92 l0022A
`
`4
`
`Approved V1.0
`
`930027411 1.0
`
`Page 3 of 10
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`
`Saxagliptin
`BMS-4771 18
`
`CRITERIA FOR EVALUATION:
`
`CV1 81039
`Final Clinical Study Report
`
`Primary Efficacy Endpoint: The change in AlC from baseline to Week 24 or the last post-baseline
`measurement pi‘ior to Week 24 and before rescue, if no VVeel< 24 assessment Was available.
`
`Secondary Effieacy Endpoints: The secondary efficacy endpoints assessed at \Veel< Z4 were:l) change
`from baseline in FPG, 2) proportion of subjects achieving AlC < 7.0%, 3) change from baseline in AUC
`from 0 to 180 minutes for PPG response to an OGTT, 4) proportion of subjects achieving AlC S 65%, and
`5) proportion of subjects requiring rescue for failing to achieve pre—specif1ed glycemic targets or
`discontinuing for lack of efficacy Within the 24 Week, short—term, double—blind treatment period. For each
`secondary efficacy endpoint, if no Week 24 measurement was available,
`then the last post—baseline
`measurement before Week 24 and before rescue (if any) was used.
`
`Other Efficacy Endpoints: Other efficacy endpoints were: l) changes from baseline to Week l2 in FPG,
`2) changes from baseline Lo Vi/eek 24 in AUCS from O to 180 minutes for postprandial insulin, glucagon,
`and C-peptide response to an OGTT, 3) change from baseline to VVeek 24 in [3-cell function (as measured
`by I-IOMA—2B), 4) change from baseline to Week 24 in insulin resistance (as measured by HOMA—2 IR), 5)
`changes from baseline to Week 24 in fasting glucagon, insulin and C-peptide, 6) changes from baseline to
`Week 24 i11 glucose, C—peptide, insulin, and glucagon concentrations at 0, 30, 60, l2(], and l80 minutes in
`response to an OGTT, 7) changes from baseline to Week 24 in the respective excursion profiles for
`glucose, C.-peptide, insulin, and glucagon concentrations, 8) changes from baseline to Vxleek 24 in the
`insulin sensitivity and [3—eell function derived from measurements of insulin, C—peptide and glucose during
`an OGTT, 9) changes from baseline to Week 24 in BMI, waist circumference, and body weight, 10)
`proportion of subjects achieving a glyceinic response at VVeek 24 based on predefined categories for AlC
`and glucose, ll) percent changes from baseline to ‘Neck 24 in total-C, LDL—C, HDL—C, TG, and FFA, 12)
`changes from baseline to Week 24 in hs—CRP, PAT-l , fibrinogen, and II.—6, and (l 3) proportion of subjects
`requiring rescue for failing to achieve pre-specified glycemic targets or discontinuing for lack of efficacy at
`Weeks 4, 6, 8, 12, 15, 20 and 24.
`
`Safety: Safety endpoints included the frequency of clinical adverse events (AEs], serious adverse events
`(SAES), and discontinuations due to AEs, as well as results for electrocardiograms (ECGS), vital signs and
`clinical laboratory tests.
`
`STATISTICAL CONSIDERATIONS:
`
`The primary endpoint was the change in AlC from baseline to Week 24 of the short-term treatment period.
`The primary efficacy analysis was performed using an analysis of covariance (ANCOVA) with treatment
`group as an effect and baseline value as the covariate. Within the framework of the ANCDVA model, point
`estimates and 95% confidence intervals were calculated for the mean changes within each treatment group
`as Well as for the differences in mean changes between the following treatment groups:
`
`0
`0
`
`Saxa Smg + Met relative to the Saxa 10mg group and relative to the Met group
`Saxa 10mg I Met group relative to Saxa 10mg group and relative to the Met group.
`
`Each combination treatment group was compared with each individual component (ie, Saxa l0mg and
`Met); each comparison was performed at the 0.027 alpha level from Dunnett"s adjustment so that the
`overall (farnilywise) Type I error rate was controlled at the 0.05 significance level. Sequential
`testing
`methodology was utilized for secondary eftieacy endpoints. At each step in the testing sequence. only the
`combination treatment group significantly superior to both controls was tested at the subsequent step.
`
`Approve.-CI, V1.0
`
`930027411 1.0
`
`Page 4 of 10
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`Page 4 of 10
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`

`
`Saxagliptin
`BMS-4771 18
`
`SUMMARY OF RESULTS:
`
`CV181039
`Final Clinical Study Report
`
`Demographics and Other Pertinent Baseline Characteristics: Demographic and baseline characteristics
`were generally balanced across all treatment groups. Oftlie 1306 treated subjects, 49% were men and 76%
`were white. The mean age was 52 years (range 19 to 77 years), and 13% of subjects were 2 65 years of age.
`The median duration oftype 2 diabetes was 0.4 years, and the mean baseline AIC was 9.5%.
`
`Extent of Exposure: The mean duration of exposure to double-blind study medication was 151 days with
`Saxa 5mg ’ 1\det, 151 days with Saxa 10mg + hlet, 137 days with Saxa 10mg and 144 days with Met.
`
`EFFICACY RESULTS: Primary and seeondaiy efficacy findings at Week 24 are shown in the following
`table.
`
`6
`
`Approved V1.0
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`930027411 1.0
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`Page 5 of 10
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`Page 5 of 10
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`Page 6 of 10
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`Page 7 of 10
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`

`
`Saxagliptin
`BN1S-4771 1 8
`
`Other Efficacy Results
`
`CV181039
`Final Clinical Study Report
`
`Combination therapy with Saxa 5mg -- Met and Saxa l {ling + Met resulted in a greater reduction from
`baseline to Week 24 for l2O minute postprandial glucose concentration relative to monotherapy (Saxa
`lOmg or Met).
`Combination therapy with Saxa 5mg -- Met and Saxa l0mg 4- Met resulted in a greater reduction from
`baseline to VVee1< l2 for FPG relative to monotherapy (Saxa 10mg or Met).
`The proportion of subjects achieving AlC glyecmic responses as assessed by predefined reductions
`trom baseline AlC after treatment for 24 weeks was consistently greater for subjects receiving
`combination therapy (Saxa Sing + Met and Saxa 10mg 7 Met) compared with inonotherapy (Saxa
`10mg or l\«1et).
`The proportion of subjects achieving predefined reductions from baseline FPG after treatment for 24
`weeks was consistently greater for subjects receiving combination therapy (Saxa 5mg + Met and Saxa
`10mg + Met) compared with monotherapy (Saxa 10mg or Met).
`Combination therapy with Saxa 5mg 1 Met and Saxa 10mg | Met resulted in a greater increase in
`B—cell function compared with monotherapy (Saxa 10mg or Met) as reflected in a greater increase
`from baseline to W661i 24 in HOMA—2B and a numerically higher increase in 30 minute insulinogenic
`index.
`
`Beginning at Week 8, numerically fewer subjects in the combination groups Saxa 5mg 1 1\/[et and Saxa
`l0mg + Met compared with the monotlierapy groups (Saxa lflmg or Met) rescued or discontinued due
`to lack ofcfficacy.
`Similar beneficial effects were seen in all treatment groups in reduction from baseline to \Veek 24 in
`weight, waist circuinference and BMI.
`
`Safety Results:
`Saxagliptin given as initial combination therapy with metformin. saxagliptin monotherapy, and metfoimin
`monotherapy were safe and Well tolerated with a similar safety profile. The following table is an overview
`of the AF, categories.
`
`Adversfi EV€"t5
`
`At least one AE
`At least one related AE
`Deaths
`At least one SAE
`At least one related SAE
`
`E/1E}](:i:‘r1t11’1l.1al1OTlS due to
`Diseontinuations due to AEs
`
`Saxa Smg
`+Met
`
`(N=32 0)
`177 (55.3)
`33 (10.3)
`0
`8 (2.5)
`1 (0.3)
`
`1 (03)
`8 (2.5)
`
`AB = adverse event; SAE = serious adverse event
`Events of hypoglycemia are included in all categories
`
`Number (" 0) of Subjects
`
`Saxa 10mg
`+ Met
`
`Saxa 10mg
`+ Pla
`
`(N=323)
`185 (57.3)
`61 (18.9)
`0
`12 (3.7)
`3 (019)
`
`3 (0.9)
`7 (2.24
`
`(N=335)
`179 (53.4)
`40 (11.9)
`0
`6 (1.8)
`0
`
`0
`8 (2.4)
`
`l\Iet
`+ Pla
`
`(N=328)
`l92 (58.5)
`59 (18.0)
`3 (0.9)
`8 (2.4)
`0
`
`1 (03)
`1 l (3.4)
`
`Approved V1.0
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`930027411 1.0
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`Page 8 of 10
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`Page 8 of 10
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`

`
`Saxagliptin
`BN1S-4771 l 8
`
`Other safety findings were:
`
`CV181039
`Final Clinical Study Report
`
`The majority of AEs were mild or moderate in intensity; approximately 3 to 5% of subjects reported
`severe or very severe Alis. The proportion of subjects reporting severe or Very severe AEs was
`highest in the Met group (5%).
`The proportion of subjects with AT.s in the SOC lnfections and lnfestations was similar in all
`treatnlent groups: Saxa Sing + Met (22.8°/6). Santa 10 mg + Met (20.1%), Saxa 10 111g (26.6%), and
`l\Iet (23.5%).
`
`The proportion of subjects with AEs in the SOC Skin and Subcutaneous Tissue Disorders was similar
`in all treatment groups: Saxa 5 mg ’ Met (3.4%), Saxa 10 mg + Met (4.3%), Saxa 10 mg (4.2%), and
`l\Ict (2.7%).
`
`O11e ease of ulceration was reported in a subject (03%) in the l\/Iet group (lip ulceration, Verbatim
`term “canker sore”).
`
`leading to discontinuation in the SOC
`The proportion of subjects reporting AEs and AEs
`Gastrointestinal Disorders and was higher in the groups receiving metformin compared with the
`saxagliptin monotherapy group.
`Cardiovascular events were infrequent: Saxa Smg + Met (0%), Saxa 10 mg + Met 2 (0.6%), Saxa
`l0 mg 4 (l.2%) and Met 3 (0.9%).
`
`AEs of lymphopenia were irifrequentz Saxa 5 mg -l-Met (0%), Saxa 10 mg + Met 3 (0.9%), Stuart
`10 mg 5 (1.5%), and Met 1 (0.3%).
`AEs ofthrombocytopenia were uncommon: Sara 5 mg +l\/let (0%), Saxa I0 mg + Met 1 (0.3%) Saxa
`10 mg 1 (0.3%), and Met 1 (0.3%).
`
`AEs of localized edema were uncommon: Saxa 5 mg + 1‘./Iet 2 (0.6%), Saxa 10 mg + Met 1 (0.3%).
`Saxa l0 mg (0%), and Met (0%).
`
`There was I case ofisolaterl toot edema in the Saxa IO mg + Met group (0.3%) in a subject who had
`this event at screening.
`AEs of confirmed hypoglycemia were uncommon: Saxa 5 mg I Met (0%), Saxa 10 mg l Met
`2 (0.6%), Saxa 10 mg (0%). and Met 1 (0.3%).
`The proportion of subjects who reported hypoglycemic AEs (all reported events) was generally
`similar in all of the treatment groups: Saxa 5 mg + lvlct ll (3.4%), Saxa l0 mg + Met l6 (5.0%),
`Saxa 10 mg 5 (1.5%), and Met 13 (4.0%).
`
`Marked abnormalities (MAS) were infrequent for any of the measured laboratory parameters, including
`hematologic, hepatic, renal, and muscle safety tests.
`The proportion of subjects with MAS for decreased lymphocyte counts (S 0.75 X '1 000 c/UL) were
`I (0.3%) in the Saxa 5 mg + Met, 5 (1.6%) in the Saxa I0 mg + Met. 3 (0.9%) in the Saxa 10 mg.
`and 0% in the Met groups.
`There were no imbalances across the treatment groups in MAs for liver function tests or creatine
`kinase.
`
`I0
`
`Approve.-CI. V1.0
`
`930027411 1.0
`
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`

`
`Saxagliptin
`BMS-4771 18
`
`CONCLUSIONS:
`
`CV181039
`Final Clinical Study Report
`
`In drug—naive subjects with type 2 diabetes, initial combination therapy with saxagliptin plus metformin for
`up to 24 Weeks was more efficacious than either agent alone. Note that there was a large magnitude of
`reduction in blood glucose concentration for all groups (saxagliptin plus mctformin combination groups
`and the saxagliptin and metformin monotlierapy groups), All treatments (combination anrl mnnotherapy
`treatments) in this study were safe and well tolerated.
`
`o
`
`0
`
`-
`
`-
`
`0
`
`0
`
`0
`
`0
`
`-
`
`The primary efficacy endpoint, mean reduction from baseline to \Neel< 24 in Al C, was statistically
`significantly larger in tl1e saxagliptin plus metformin combination treatment groups compared with
`both saxagliptin and metformin monotherapy treatment groups
`Saxagliptin plus metformin combination therapy led to a statistically significant greater decrease
`from baseline relative to saxagliptin and metforrnin monotherapy in mean FPG and postprandial
`glucose AUC, and also a higher proportion of subjects achieving AIC < 7.0% or S 6.5%.
`
`Saxagliptin plus metformin combination therapy was associated with further improved B-cell
`function relative to monotherapy.
`The proportion of subjects reporting AEs and SAEs or discontinuing due to an AB in the
`saxagliptin plus metfoirnin combination groups was similar to either saxagliptin or metformin
`monotherapy.
`The frequency of hypoglycemia with saxagliptin plus metforrnin combination therapy was similar
`compared with saxagliptin and metformin monotl1erapy even with significantly greater glycemic
`efficacy demonstrated by initial combination treatment.
`Cardiovascular events were infrequent and balanced in frequency among the treatment groups‘
`
`No events believed to be retlective of clinical correlates in humans of skin-related findings seen in
`saxagliptin-treated monkeys were observed in the type 2 diabetic subjects treated with saxagliptin
`in this trial.
`
`Similar degrees of weight loss were observed in subjects receiving saxagliptin plus metformin
`combination therapy, saxagliptin monotherapy, and metformin monotherapy.
`
`A small increase in the proportion of subjects with AEs and marked abnormalities for lymphocyte
`reduction was associated with saxagliptin 10 mg (given either as combination therapy with
`metformin or as monotherapy), with no evident clinical sequelae. Other laboratory parameters
`measured, including hematologic, hepatic, renal, and muscle safety tests, showed no drug-related
`safety signal.
`
`DATE OF REPORT: 21-Apr-2008
`
`I
`
`l
`
`Approve.-CI, V1.0
`
`930027411 1.0
`
`Page 10 of 10
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