1
`
`Reference P006
`
`An Open-Label, Randomized, 2-Period, Single-Dose Crossover
`Study to Investigate the Influence of Formulation on MK-0431
`Pharmacokinetics in Healthy Male or Female Subjects
`
`Merck Exhibit 2107, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MK-0431, Reference P006
`
`2
`
`Reference P006
`
`Healthy Subject PK and Tolerability Study Report
`
`CLINICAL STUDY REPORT
`
`MK-0431
`
`An Open-Label, Randomized, 2-Period, Single-Dose Crossover Study to
`Investigate the Influence of Formulation on MK-0431 Pharmacokinetics
`in Healthy Male or Female Subjects
`
`Generic Name:
`Dosage Form: MK-0431 Capsule and
` MK-0431 Tablet
`Indication: Diabetes
`
`Sponsor Name: Merck & Co., Inc.
`Clinical Monitor: Dr. Gary Herman
`Study Initiation Date (FPI):
`Study Completion Date (LPO):
`
`Investigator Name/Affiliation:
`
`GCP Compliant? y/n
`
`Protocol 006
`Phase I
`
`Study Design: Open, 2-Period, Single-
`Dose, Crossover, Comparative
`Bioavailability Study
`
`11-Nov-2002
`03-Dec-2002
`
`Dr. Suzanne K. Swan
`DaVita Clinical Research
`825 S. 8th Street, Suite 300
`Minneapolis, Minnesota 55404
`Yes
`
`Clinical Study Report Date
`
`11-Mar-2005
`
`CSR Title Page_0431_006_P006 VERSION 2.2 APPROVED
`Restricted Confidential – Limited Access
`
`25-Mar-2005
`
`Merck Exhibit 2107, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MK-0431, Reference P006
`
`3
`
`CLINICAL STUDY REPORT
`
`An Open-Label, Randomized, 2-Period, Single-Dose Crossover Study to
`Investigate the Influence of Formulation on MK-0431 Pharmacokinetics
`in Healthy Male or Female Subjects
`
`TABLE OF CONTENTS
`
`3.
`
`I. SYNOPSIS
`II. COMPREHENSIVE STUDY SUMMARY
`1.
`INTRODUCTION
`2. ETHICS
`2.1
`Institutional Review Board (IRB)
`2.2 Ethical Conduct of the Study
`2.3 Subject Information and Informed Consent Form
`INVESTIGATORS AND STUDY ADMINISTRATIVE
`STRUCTURE
`4. STUDY HYPOTHESES AND OBJECTIVES
`4.1 Hypotheses
`4.2 Objectives
`INVESTIGATIONAL PLAN
`5.1 Overall Study Design and Plan: Description
`5.2 Discussion of Study Design, Including the Choice of
`Control Groups
`5.3 Selection of Study Population
`5.3.1
`Inclusion Criteria
`5.3.2 Exclusion Criteria
`5.3.3 Discontinuation of Subject from Therapy or Study
`Observation
`5.4 Treatments
`5.4.1 Treatments Administered and Special Diet
`Administered
`
`5.
`
`Application
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`13
`15
`15
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`15
`
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`16
`16
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`21
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`21
`22
`22
`24
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`24
`24
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`IPR2020-00040
`
`

`

`MK-0431, Reference P006 (Cont.)
`
`4
`
`TABLE OF CONTENTS (CONT.)
`
`Identity of Clinical Supplies
`5.4.2
`5.4.3 Method of Assigning Subjects to Treatment
`Groups
`5.4.4 Selection of Doses and Timing of Dose for Each
`Subject
`5.4.5 Study Blinding Procedure
`5.4.6 Prior and Concomitant Therapies
`5.4.7 Treatment Compliance
`5.5 Pharmacokinetic, Safety and Tolerability Parameters
`5.5.1 Measurements Assessed and Timing of
`Assessment
`5.5.1.1 Safety Measurements
`5.5.2 Appropriateness of Measurements
`5.5.3 Primary and Secondary Parameter(s)
`5.5.4 Blood for Plasma MK-0431 Drug Concentration
`Measurements
`5.5.5 Analytical Methods
`5.5.6 Pharmacokinetic Methods
`5.6 Data Quality Assurance
`5.7 Statistical Methods Planned in the Protocol and
`Determination of Sample Size
`5.7.1 Statistical and Analytical Plans to Address Study
`Objectives
`5.7.2 Determination of Sample Size and Power
`Analysis to Address Study Hypothesis
`5.7.3 Statistical/Analytical Methods and Issues
`5.8 Changes in the Conduct of the Study or Planned
`Analyses
`6. STUDY AND DATA SETS ANALYZED
`6.1 Accounting for Subjects in the Study
`6.2 Protocol Deviations
`6.3 Subjects Whose Treatment Was Prematurely Unblinded
`
`Application
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`24
`27
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`27
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`27
`28
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`28
`29
`29
`29
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`30
`30
`30
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`32
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`32
`32
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`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MK-0431, Reference P006 (Cont.)
`
`5
`
`TABLE OF CONTENTS (CONT.)
`
`6.4 Efficacy Populations Analyzed
`6.5 Demographic and Other Baseline Characteristics
`6.5.1 Baseline Characteristics
`6.5.2 Secondary Diagnoses
`6.5.3 Prior Therapies
`6.5.4 Procedures
`6.6 Concomitant Therapies
`6.7 Measurements of Treatment Compliance
`7. PHARMACOKINETICS AND BIOAVAILABILITY
`EVALUATION AND RESULTS
`7.1 Pharmacokinetics
`8. SAFETY EVALUATION
`8.1 Extent of Exposure
`8.2 Clinical Adverse Experiences
`8.2.1 Brief Summary of Clinical Adverse Experiences
`8.2.2 Display of Clinical Adverse Experiences
`8.2.3 Analysis of Clinical Adverse Experiences by
`Body System
`8.2.3.1 Drug-related Clinical Adverse Experiences
`8.3 Serious Clinical Adverse Experiences
`8.3.1 Subjects Who Discontinued Due to Clinical
`Adverse Experiences
`8.4 Special Safety Analyses
`8.5 Laboratory Adverse Experiences
`8.6 Clinical Evaluation of Laboratory Safety Tests
`8.7 Vital Signs, and Other Physical Observations Related
`to Safety
`9. DISCUSSION
`10. OVERALL EFFICACY AND SAFETY CONCLUSIONS
`11. SUPPLEMENTAL TABLES, FIGURES, AND/OR
`NARRATIVES
`
`Application
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`44
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`Merck Exhibit 2107, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MK-0431, Reference P006
`
`6
`
`MK-0431 Prot. No. 006
`Comparative Bioavailability
`
`LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
`
`Abbreviation
`
`
`
`
`
`Definition
`
`
`AN
`ANOVA
`ANCOVA
`AUC
`B.I.D.
`BBB
`BMI
`BP
`BUN
`CI
`ClR
`Cmax
`C24
`CSS
`CSR
`CV
`CYP
`DAP
`DCCT
`DPPIV
`ECG
`FSG
`GI
`GMR
`GIP
`GLP-1
`HbA1C
`hCG
`HR
`HRT
`IM
`IN
`IP
`IUD
`IV
`LS means
`MED
`MRL
`mse
`NSAID
`OGGT
`OTC
`PD
`
`Allocation number
`Analysis of variance
`Analysis of covariance
`Area under the concentration-time curve
`Twice daily
`Blood-brain barrier
`Body mass index
`Blood pressure
`Blood urea nitrogen
`Confidence interval
`Renal Clearance
`Maximum concentration
`Concentration at 24 hours
`Clinical study summary
`Clinical study report
`Coefficient of variation
`Cytochrome P450 liver microsome
`Data analysis plan
`Diabetes control and complications trial
`Dipeptidyl-peptidase IV
`Electrocardiogram
`Fasting serum glucose
`Gastrointestinal
`Geometric mean ratio
`Gastric inhibitory peptide
`Glucagon-like peptide-1
`Hemoglobin A1c
`Human chorionic gonadotropin
`Heart rate
`Hormone replacement therapy
`Intramuscular
`Intranasal
`Intraperitoneal
`Intrauterine device
`Intravenous
`Least-squares means
`Minimal effective dose
`Merck Research Laboratories
`Mean square error
`Nonsteroidal anti-inflammatory drug
`Oral glucose tolerance test
`Over the counter
`Pharmacodynamic(s)
`
`CSR List of Abbreviations_0431_006_P006 VERSION 2.1 APPROVED
`Restricted Confidential – Limited Access
`
`25-Mar-2005
`
`Merck Exhibit 2107, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MK-0431, Reference P006 (Cont.)
`
`7
`
`MK-0431 Prot. No. 006
`Comparative Bioavailability
`
`Abbreviation
`
`
`
`Definition
`
`PK
`Q.D.
`RBC
`SC
`SD
`SEM
`(SGOT) AST
`(SGPT) ALT
`Tmax
`UKPDS
`ULN
`WBC
`
`Pharmacokinetic(s)
`Once daily
`Red blood (cell) count
`Subcutaneous
`Standard deviation
`Standard error of the mean
`Aspartate aminotransferase test
`Alanine aminotransferase test
`Time of maximum concentration
`United Kingdom prospective diabetes study
`Upper limit of normal
`White blood (cell) count
`
`CSR List of Abbreviations_0431_006_P006 VERSION 2.1 APPROVED
`Restricted Confidential – Limited Access
`
`25-Mar-2005
`
`Merck Exhibit 2107, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`MK-0431, Reference P006
`
`8
`
`LIST OF TABLES
`
`Table 5-1
`
`Table 5-2
`Table 5-3
`Table 5-4
`Table 5-5
`
`Table 6-1
`Table 7-1
`
`Table 7-2
`
`Table 7-3
`
`Table 7-4
`
`Table 8-1
`
`Schedule of Clinical Observations and Laboratory
`Measurements For Each Period
`Laboratory Safety Analyses
`Treatment Sequence
`Clinical Supplies
`Composition and Analytical Measurements for
`Tablet and Capsule MK-0431 Formulations
`Baseline Subject Characteristics
`Individual and Mean MK-0431 Plasma
`Pharmacokinetic Parameters Following Single
`Oral 50-mg Doses of MK-0431 Administered in
`the Tablet or Capsule Formulation to Healthy Male
`and Female Subjects
`Summary Statistics for MK-0431 AUC0-∞ (µMchr)
`and Cmax (nM) Following Administration of
`Single Oral 50 mg Doses of Either Tablet or
`Capsule Formulations of MK-0431 in 12 Healthy
`Subjects
`Summary Statistics for MK-0431 Tmax (hr)
`Following Administration of Single Oral 50 mg
`Doses of Either Tablet or Capsule Formulations of
`MK-0431 in 12 Healthy Subjects
`Summary Statistics for MK-0431 Apparent t1/2
`(hr) Following Administration of Single Oral 50
`mg Doses of Either Tablet or Capsule Formulations
`of MK-0431 in 12 Healthy Subjects
`Listing of Patients With Clinical Adverse
`Experiences
`
`Application
`Starting
`Page
`
`18
`
`20
`21
`25
`26
`
`33
`36
`
`37
`
`38
`
`39
`
`41
`
`Merck Exhibit 2107, Page 8
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`IPR2020-00040
`
`

`

`MK-0431, Reference P006
`
`9
`
`LIST OF FIGURES
`
`Figure 7-1 Mean MK-0431 Plasma Concentrations Following
`Single Oral 50-mg Doses of MK-0431 Administered in
`the Tablet and Capsule Formulations to Healthy Male and
`Female Subjects (N=12)
`
`Application
`Starting
`Page
`
`35
`
`Merck Exhibit 2107, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`10
`
`MERCK RESEARCH
`LABORATORIES
`
`CLINICAL STUDY REPORT
`I. SYNOPSIS
`
`MK-0431 Dry Filled Capsule
`MK-0431 Film Coated Tablet
`Diabetes-Type 2 Diabetes
`
`PROTOCOL TITLE/NO.: An Open-Label, Randomized, 2-Period, Single-Dose
`Crossover Study to Investigate the Influence of Formulation on MK-0431
`Pharmacokinetics in Healthy Male or Female Subjects
`INVESTIGATOR/STUDY CENTER: Dr. Suzanne K. Swan/DaVita Clinical Research, 825 S. 8th Street,
`Suite 300, Minneapolis, Minnesota, 55404.
`PRIMARY THERAPY PERIOD: 11-Nov-2002 to 12-Dec-2002
`DURATION OF TREATMENT: Single doses of 50 mg in each period
`OBJECTIVES: Primary: To compare the Phase II formulation (tablet) relative to the Phase I
`formulation (capsule) with respect to MK-0431 pharmacokinetic parameters [AUC(0-∞), Cmax, C24, Tmax,
`and apparent half-life (t½)]. Secondary: To assess the safety and tolerability of single oral doses of the
`tablet formulation of MK-0431.
`STUDY DESIGN: This was an open-label, randomized, 2-period, crossover study in which 12 male and
`female subjects were randomized to the sequence of treatment in which they received 50 mg (1 x
`50 mg) of MK-0431 as either the tablet formulation or the dry filled capsule formulation, separated by a
`washout interval of 7 days between doses. Each single-dose administration was followed by collection
`of blood samples through 72 hours postdose in each period. Safety and tolerability was assessed by
`tabulating adverse experiences and by clinical, electrocardiogram (ECG) and laboratory assessment.
`Subjects were confined to the clinical research unit for the first 32 hours of the study in each period. At
`the discretion of the investigator, subjects could leave the study unit after the 24-hour postdose
`procedures and return to the clinical research unit for their 32-hour and subsequent procedures.
`SUBJECT DISPOSITION:
`
`
`#006
`
`CLINICAL PHASE:
`
` I
`
`
`
`
`
` Total
`
`
`
`
`12
`ENTERED: Total
`
`6 (21 to 43)
`Male (age range)
`
`6 (18 to 56)
`Female (age range)
`
`12
`COMPLETED:
`
`
`0
`
`DISCONTINUED:
`DOSAGE/FORMULATION NOS: The details on the formulations used in this study are presented
`below.
`
`
`
`
`
`
`
`
`
`
`
`
`Clinical Supplies
`
`Drug
`
`
`
`MK-0431
`MK-0431
`
`Potency
`
`50 mg
`50 mg
`
`Formulation No.
`
`0431DFC001H001
`0431FCT001B001
`
`Dosage Form
`
`
`Dry Filled Capsule
`Film Coated Tablet
`
`Control
`Number
`
`WP-K508
`WP-K509
`
`DIAGNOSIS/INCLUSION CRITERIA: Male and female subjects, 18 to 56 years of age.
`EVALUATION CRITERIA:
`PHARMACOKINETICS: Plasma AUC(0-∞), Cmax, Tmax, and apparent t½ were derived from time-
`concentration profiles of MK-0431 in plasma following administration of 50-mg dry filled capsules
`(used in Phase I) and film coated tablets (used in Phase IIB) as appropriate. The primary endpoints in
`this study were AUC(0-∞), Cmax, Tmax, C24hr, and apparent terminal half-life (t½).
`SAFETY: Safety and tolerability of MK-0431 was evaluated by vital signs, physical examination,
`12-lead ECG, and laboratory safety parameters (hematology, chemistry, and urinalysis) at selected
`time points and tabulating adverse experiences and by the assessment of the clinical significance of
`changes in the laboratory data throughout the study.
`
`CSR Synopsis_0431_006_P006 VERSION 2.2 APPROVED
`Restricted Confidential – Limited Access
`
`01-Apr-2005
`
`Merck Exhibit 2107, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`11
`
`MERCK RESEARCH
`LABORATORIES
`
`MK-0431 Dry Filled Capsule
`MK-0431 Film Coated Tablet
`Diabetes-Type 2 Diabetes
`
`CSR Synopsis (Cont.)
`Protocol 006
`
`-2-
`
`STATISTICAL PLANNING AND ANALYSIS:
`
`
`PHARMACOKINETICS: An analysis of variance (ANOVA) model appropriate for a 2-period
`crossover design was used to compare the tablet formulation (used in Phase IIB) relative to the
`capsule formulation (used in Phase I) with respect to MK-0431 pharmacokinetic parameters (AUC0-∞,
`Cmax, C24hr) when single oral doses of 50-mg MK-0431 were administered as the different
`formulations. The ANOVA model contained factors for sequence, subject within sequence, period,
`and treatment. The geometric mean ratios (GMR) of comparison (tablet/capsule) for AUC0-∞, Cmax and
`C24hr of MK-0431 and their 90% confidence intervals (CI) were computed. The 90% CI for AUC0-∞
`was then compared against the prespecified comparability bounds of (0.70, 1.43).
`
`Pharmacokinetic parameters Tmax and apparent t1/2 were also analyzed using the same ANOVA model
`as described above. Prior to statistical analysis, a log transformation was applied to the AUC0-∞, Cmax
`and C24hr data; a rank transformation was applied to the Tmax data; an inverse transformation was
`applied to the apparent t1/2 data.
`SAFETY: Safety information was evaluated by tabulating adverse experiences and by clinical
`assessment of laboratory, ECG and vital signs data. Adverse experiences were evaluated as to their
`intensity, seriousness, and relationship to study drug.
`RESULTS:
`PHARMACOKINETICS: The pharmacokinetics of MK-0431, assessed as AUC0-∞, Cmax, C24hr, Tmax
`and apparent t1/2 were generally similar for tablet formulation (used in Phase IIB) as compared to the
`capsule formulation (used in Phase I) of MK-0431. The AUC0-∞ GMR (tablet/capsule) following
`single oral doses of 50 mg of either tablet (used in Phase IIB) or capsule (used in Phase I) was 1.04
`with a 90% CI of (1.02, 1.07), which fell within the prespecified bounds of [0.70, 1.43]. The Cmax for
`the tablet formulation (used in Phase IIB) was slightly elevated (approximately 20%) and had a
`marginally statistically significant shorter Tmax compared to the capsule formulation (used in Phase I).
`The C24hr and apparent terminal t1/2 were not meaningfully different between the 2 formulations.
`Summary statistics for pharmacokinetic parameters of tablet (used in Phase IIB) and capsule
`formulation (used in Phase I) are in the table below.
`
`CSR Synopsis_0431_006_P006 VERSION 2.2 APPROVED
`Restricted Confidential – Limited Access
`
`01-Apr-2005
`
`Merck Exhibit 2107, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`12
`
`MERCK RESEARCH
`LABORATORIES
`
`MK-0431 Dry Filled Capsule
`MK-0431 Film Coated Tablet
`Diabetes-Type 2 Diabetes
`
`CSR Synopsis (Cont.)
`Protocol 006
`
`-3-
`
`Summary Statistics for MK-0431 Pharmacokinetic Parameters Following Administration of
`Single Oral Doses of 50-mg Tablet Formulation (used in Phase IIB) or Capsule Formulation
`(used in Phase I) of MK-0431 in 12 Healthy Male and Female Subjects
`
`Parameter
`
`Tablet
`Formulation
`Geometric Mean
`
`4.42
`435
`40.0
`3.0†
`14.2‡
`
`
`AUC0-∞ (µM•hr)
`Cmax (nM)
`C24hr (nM)
`Tmax (hr)
`Apparent t1/2 (hr)
`† Median.
`‡ Harmonic Mean.
`§ p-Value.
` Tablet Formulation (used in Phase IIB).
`¶ Capsule Formulation (used in Phase I).
`
`Capsule¶
`Formulation
`Geometric Mean
`
`4.23
`360
`40.5
`4.5†
`13.8‡
`
`Tablet/
`Capsule¶
`GMR (90% CI)
`
`1.04 (1.02, 1.07)
`1.21 (1.10, 1.33)
`0.99 (0.95, 1.03)
`0.062§
`0.529§
`
`SAFETY: A total of 5 subjects (3 while receiving the capsule formulation [used in Phase I] and 2
`while receiving the tablet formulation [used in Phase IIB]) had one or more adverse experiences
`following dosing. The most frequent adverse experience in each group while on treatment was
`headache. For 4 subjects, 2 in each group, the adverse experiences were considered possibly drug
`related by the investigator. The adverse experiences were rated as mild during the study. No subject
`discontinued the study due to an adverse experience. No subject had a serious adverse experience.
`
`Two subjects had a slightly increased value of serum potassium (hyperkalemia) at 24 hours postdose
`that the investigator reported as a possibly drug related adverse laboratory experience (values of 5.3
`and 5.2 mmol/l with an upper limit of normal of 5.1 mmol/l). Neither was rated as serious or
`required any action with regard to the study drug. Neither subject was discontinued in the study.
`Both incidents occurred in Period 1 of their respective treatments, one while receiving the tablet
`(used in Phase IIB) and one after receiving the capsule (used in Phase I). Serum potassium values
`subsequently returned to within normal limits prior to treatment in the next dosing period. Neither
`subject demonstrated an increase following their crossover to the next period where they received the
`other formulation.
`CONCLUSIONS: (1) The pharmacokinetics of MK-0431 are similar when administered as either a dry
`filled capsule formulation (used in Phase I) or the film-coated tablet formulation (used in Phase IIB).
`(2) MK-0431 is generally well tolerated when administered as a single 50-mg dose as either a dry filled
`capsule formulation (used in Phase I) or a film-coated tablet formulation (used in Phase IIB).
`AUTHORS:
` David L. Ebel, B.A., B.S.
`Wei Zheng, M.S.
`Clinical Associate
`Statistician
`Clinical Pharmacology
`CBARDS
`
`Rajesh Krishna, Ph.D., FCP
`Associate Director
`Clinical Pharmacology
`
`Arthur Bergman, Ph.D.
`Research Fellow
`Drug Metabolism
`
`Gary Herman, M.D.
`Director
`Clinical Pharmacology
`
`CSR Synopsis_0431_006_P006 VERSION 2.2 APPROVED
`Restricted Confidential – Limited Access
`
`01-Apr-2005
`
`Merck Exhibit 2107, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`13
`
`MK-0431 Prot. No. 006
`Comparative Bioavailability
`
`-1-
`
`II. COMPREHENSIVE STUDY SUMMARY
`
`1.
`
`INTRODUCTION
`
`Type 2 diabetes accounts for more than 90% of all diabetes. This disorder afflicts an
`estimated 6% of the adult population in Western society and over 2% worldwide.
`The worldwide prevalence of type 2 diabetes is increasing and expected to grow by
`3% per annum, reaching an expected total of 210 million cases by 2010. Although
`the DCCT and UKPDS trials have shown that intensive treatment of hyperglycemia
`leads to a lower incidence of microvascular complications (e.g., retinopathy and
`nephropathy), many patients remain inadequately treated using existing therapies.
`Shortcomings of current therapies include limited extent and/or durability of
`efficacy, inconvenience in dosing regimens and safety and tolerability issues
`[1.1.1] 1 . The most common adverse effects are hypoglycemia (sulfonylureas,
`meglitinides, insulin), weight gain (sulfonylureas, meglitinides, insulin, TZDs), and
`gastrointestinal intolerance (metformin, alpha-glucosidase inhibitors). There is a
`need for additional medical therapies with distinct mechanisms of action that offer
`improved efficacy and/or durability with an improved safety and tolerability profile.
`
`The pathogenesis of type 2 diabetes involves a set of 3 primary defects: insulin
`resistance, insulin sectary dysfunction, and hepatic glucose overproduction [1.1.2].
`Therapeutic agents that increase the circulating concentrations of insulin have proven
`beneficial in the treatment of type 2 diabetes. Following a meal, gut-derived hormones
`known as incretins are released into the circulation, leading to enhanced insulin
`secretion. Two such factors, glucagon-like peptide-1 (GLP-1) and Gastric Inhibitory
`Peptide (GIP), are believed to account for the majority of the incretin response.
`Although the incretin response may be impaired in type 2 diabetics, the response to
`GLP-1 appears to be intact [1.1.3]. Both GLP-1 and GIP are inactivated by the
`dipeptidyl peptidase-IV (DPP-IV), therefore inhibition of DPP-IV activity can
`stabilize and hence increase incretin concentrations.
`
`DPP-IV inhibitors are a new potential therapeutic approach to the treatment of type 2
`diabetes that function, at least in part, as indirect stimulators of insulin secretion via
`enhancement of incretin concentrations. This effect is believed to be primarily
`mediated via stabilization of GLP-1. GLP-1 has a clearly established role in
`glucose-dependent insulin biosynthesis and secretion [1.1.4 to 1.1.6]. Injection of
`GLP-1 analogs or continuous infusion of GLP-1 to patients with type 2 diabetes
`results in improvements in postprandial glucose and fasting plasma glucose [1.1.4 to
`1.1.7]. For instance, sub-chronic (6-week) continuous infusion of GLP-1 resulted in
`clinically significant decreases in fasting plasma glucose (14.1 to 10.1 mM) and
`HbA1C (from 9.2 to 7.9%) as compared to placebo [1.1.8].
`
`1 Refer to List of Appendices. Within a bracket, the first number refers to an Appendix Category, the
`second number refers to an Appendix within that Category, and the third number (optional) refers to a
`document within the Appendix, e.g., [1.1.3] = Appendix Category 1, Appendix 1, Document No. 3.
`
`RC4079.DOC VERSION 3.2 APPROVED
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`Comparative Bioavailability
`
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`
`DPP-IV inhibitors have at least 3 theoretical advantages over currently available
`insulin secretagogues. First, because preclinical studies indicate that GLP-1 and
`other incretins increase insulin secretion in a strictly glucose-dependent manner, in
`theory, there may be less risk of hypoglycemia than that observed with insulin,
`sulfonylureas or meglitinides. Second, based on preliminary experiments in DPP-IV
`knockout mice (demonstrating resistance to diet-induced obesity), and analogous to
`what is observed with other GLP-1-based therapies, little or no weight gain is
`anticipated with DPP-IV inhibitors. Finally, because of potential trophic effects of
`GLP-1 and other incretins on pancreatic beta-cells and since DPP-IV inhibitors have
`been shown to improve pancreatic beta-cell function in chronic rodent models of
`diabetes [1.1.9; 1.1.10], increased durability of therapeutic effects may be observed
`with DPP-IV inhibitors.
`
`MK-0431 is an orally active, potent and selective DPP-IV inhibitor proposed for the
`treatment of type 2 diabetes mellitus. Administration of MK-0431 to rodents results
`in DPP-IV inhibition, elevation in active GLP-1 levels and profound reductions in
`postchallenge glucose following administration of oral glucose tolerance tests. In
`these preclinical rodent models, inhibition of plasma DPP-IV activity of 80% or
`greater and/or augmentation of post-challenge active GLP-1 levels by 2-fold or
`higher is associated with maximal or near-maximal acute lowering of glycemic
`excursion.
`
`Rationale for the Present Study
`
`Phase I clinical studies investigating the pharmacokinetics and pharmacodynamics
`of MK-0431 have employed a formulation where the drug was dry-filled into
`capsules. For continued development, a tablet formulation of MK-0431 was
`considered necessary. A film-coated tablet manufactured by direct compression has
`been developed for this purpose. Significant differences in bioavailability were not
`expected between the 2 formulations given the similarities in the dissolution profiles
`and the known physicochemical properties of MK-0431 (Table 5-5). The present
`study compared the single dose pharmacokinetic profile of MK-0431 following
`administration of the tablet (used in Phase IIB) and the capsule (used in Phase I)
`formulation. It was expected that information obtained from this study would bridge
`Phase I pharmacokinetic data and provide a basis for dose selection in Phase II using
`the new tablet formulation. A dose of 50 mg was selected based on the predicted
`clinical dose range considerations based on available data and approximately dose-
`proportional pharmacokinetics with respect to total exposure. Given the exploratory
`nature of this investigation designed to assist formulation development, formal
`bioequivalence confidence intervals were not employed.
`
`RC4079.DOC VERSION 3.2 APPROVED
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`MK-0431 Prot. No. 006
`Comparative Bioavailability
`
`-3-
`
`2. ETHICS
`
`2.1
`
`Institutional Review Board (IRB)
`
`The study protocol and subject consent procedures were reviewed and approved by:
`
`Human Subjects Research Committee
`Hennepin County Medical Center
`914 South Eighth Street
`900 HFA Building
`Minneapolis, Minnesota 55404
`
`2.2 Ethical Conduct of the Study
`
`This study was conducted in conformance with applicable country or local
`requirements regarding ethical committee review, informed consent, and other
`statutes or regulations regarding the protection of the rights and welfare of human
`subjects participating in biomedical research.
`
`2.3 Subject Information and Informed Consent Form
`
`Prior to the screening visit, the investigator or his staff read and explained the
`informed consent to all subjects. The consent form was signed by each subject and
`the person conducting the interview, and each subject was given a signed and dated
`copy. A copy of the informed consent is in [3.4].
`
`3.
`
`INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
`
`The study was conducted at a single center. The name and address of the Primary
`Investigator and the Ethics Review Committee and its Committee Chair is listed
`below. The primary investigator’s curriculum vitae is in [3.6].
`
`Primary Investigator/Address
`
`Dr. Suzanne K. Swan,
`DaVita Clinical Research, 825 S. 8th Street, Suite 300
`Minneapolis, Minnesota, 55404
`
`Institutional Review Board
`
`Human Subjects Research Committee
`Hennepin County Medical Center
`914 South Eighth Street
`900 HFA Building
`Minneapolis, Minnesota 55404
`
`RC4079.DOC VERSION 3.2 APPROVED
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`
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`16
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`MK-0431 Prot. No. 006
`Comparative Bioavailability
`
`-4-
`
`Committee Chair
`
`Frederick Langendorf, M.D. Chairman
`Karen Hemi-Duthoy, Pharm. D. Vice Chair
`
`4. STUDY HYPOTHESES AND OBJECTIVES
`
`4.1 Hypotheses
`
`The plasma MK-0431 AUC(0-∞) following a single dose of a 50-mg [1 x 50-mg]
`MK-0431 tablet formulation will be similar to the plasma AUC(0-∞) following a
`single dose of a 50-mg [1 x 50-mg] MK-0431 capsule formulation [the geometric
`mean ratio will be no less than 0.70 and no greater than 1.43].
`
`4.2 Objectives
`
`Primary
`
`To compare the Phase II formulation tablet relative to the Phase I formulation
`(capsule) with respect to MK-0431 pharmacokinetic parameters [AUC(0-∞), Cmax,
`C24hr, Tmax, and apparent half-life (t½)].
`
`Secondary
`
`To assess the safety and tolerability of single oral doses of the tablet formulation of
`MK-0431.
`
`5.
`
`INVESTIGATIONAL PLAN
`
`5.1 Overall Study Design and Plan: Description
`
`The protocol is in [3.3] and a sample case report form is in [3.5].
`
`The primary treatment period was 11-Nov-2002 to 12-Dec-2002.
`
`The in-house cutoff date for case report forms was 10-Sep-2004.
`
`This was an open-label, 2-period, randomized, crossover study to assess the
`pharmacokinetics, safety, and tolerability of MK-0431 as the tablet formulation
`(used in Phase IIB) as compared to the dry filled capsule formulation (used in Phase I).
`
`Twelve adult subjects were randomized to the sequence of treatment ordering in
`which they received 50 mg (1 x 50 mg) of MK-0431 as either the tablet formulation
`(used in Phase IIB) or the dry filled capsule formulation (used in Phase I),
`separated by a washout interval of 7 days between doses.
`
`RC4079.DOC VERSION 3.2 APPROVED
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`
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`17
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`Comparative Bioavailability
`
`-5-
`
`Each single-dose administration was followed by collection of blood samples
`through 72 hours postdose in each period. Plasma was assayed for MK-0431
`concentrations.
`
`Safety and tolerability was assessed by tabulating adverse experiences and by
`clinical, Electrocardiogram (ECG) and laboratory assessment. Subjects were confined
`to the unit for the first 32 hours of each period of the study. At the discretion of the
`investigator subjects could leave the Clinical Research Unit after the 24-hour
`procedures but must return for their 32-hour and subsequent procedures.
`
`The schedule of clinical observations and laboratory measurements is listed in
`Table 5-1 and a list of laboratory tests performed is presented in Table 5-2.
`
`RC4079.DOC VERSION 3.2 APPROVED
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`
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`
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`
`

`

`MK-0431 Prot. No. 006
`Comparative Bioavailability
`
`-6-
`
`Schedule of Clinical Observations and Laboratory Measurements For Each Period
`
`Table 5-1
`
`
`
`
`Procedures
`
`
`Review entry criteria/IC/
`medical history
`Urine for drug screen‡
`Laboratory safety tests
`HIV screen
`Serum β-hCG
`Urine β-hCG§
`Physical exam, weight
`RR, oral temperature
`Vital signs (BP, HR) ¶
`12-lead ECG
`Administration of MK-0431#
`
`
`
`
`
`Prestudy Predose
`
`
`X
`
`
`0 0.5
`
`
`
`
`
`
`1
`
`
`
`X
`X
`X
`X
`
`X
`X
`X
`X
`
`
`
`X
`
`
`X
`
`X
`X
`X
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`
`
`
`
`
`
`
`
`
`X
`
`
`
`3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Periods 1 and 2
`Hours Postdose
`6
`8
`10 12
`
`
`
`
`
`
`
`
`
`15 18
`
`
`
`
`
`24 32
`
`
`
`
`
`48 72 Poststudy†
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`
`
`X
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`
`
`X
`X
`X
`X
`X
`
`
`18
`
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`

`

`Table 5-1 (Cont.)
`
`Schedule of Clinical Observations and Laboratory Measurements For Each Period
`
`-7-
`
`MK-0431 Prot. No. 006
`Comparative Bioavailability
`
`
`
`
`Procedures
`
`
`
`
`
`Prestudy Predose
`
`
`
`X
`
`
`
`Periods 1 and 2
`Hours Postdose
`48 72 Poststudy†
`24 32
`15 18
`6
`8
`10 12
`5
`4
`3
`2
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X X X X X X X X X X X X X
`
`X
`X X X
`
`X-----------------------------------------------------------------------------------------------------------------------------X
`
`0 0.5
`
`
`1.5
`
`
`Plasma for MK-0431
`Evaluation of adverse
`experiences
`† Poststudy Visit 12 to 14 days after the last test drug administration. Follow-up for any adverse events occurred 2 weeks after dosing by phone or in person.
`‡ Urine for narcotics, stimulants, benzodiazepines, cocaine, and marijuana.
`§ Urine β-hCG (pregnancy test) for women of childbearing potential was done within 24 hours predose of each period, and poststudy (12 to 14) days following the
`last dose.
` Body weight was measured with shoes for determination if the subject meets the inclusion criteria. The subjects weight with shoes removed was also be recorded.
`¶ Heart rate (HR) and blood pressure (BP) obtained in the supine position. See Appendix 6.
`# MK-0431 administration is performed after at least an 8-hour overnight fast (except water).
`Data Source: [3.3]
`
`19
`
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`

`20
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`MK-0431 Prot. N