Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`TITLE PAGE
`
`Salix
`
`PHARMACEITTECALS, INC.
`ADVANCING TIKATMENf IN GASTROENTIROOGY
`
`Salix Pharmaceuticals, Inc.
`
`CLINICAL STUDY REPORT
`
`The Relative Absorption and Disposition of 5-Aminosalicylic Acid
`Administered in the Fasting State to Healthy Human Subjects: Comparison
`Between 800 mg Asacol® Twice Daily, 800 mg Mesalamine Pellet Formulation
`Twice Daily, and 1600 mg Mesalamine Pellet Formulation Once Daily
`
`Name of Test/Investigational Drug:
`Indication Studied:
`Phase of Study:
`Protocol Number:
`
`Mesalamine
`N/A; pharmacokinetic study
`1
`MPPK1001
`
`Study Initiation Date:
`Study Completion Date:
`
`30 December 2003 (first consent signed
`13 February 2004
`
`Date of Study Report:
`
`01 October 2007
`
`Study Sponsor:
`
`Name of Sponsor Signatory:
`
`Salix Pharmaceuticals, Inc
`1700 Perimeter Park Drive
`Morrisville, North Carolina, USA 27560
`Tel: (919) 862-1000 and Fax: (919) 862-1095
`
`William P. Forbes, PharmD
`Vice President of Research and Development &
`Chief Development Officer
`Salix Pharmaceuticals, Inc.
`
`This study was performed in compliance with Good Clinical Practices (GCP). All records are
`kept at Salix Pharmaceuticals, Inc.
`
`Confidential Information—Subject to Protective Order
`
`SALI X00378802
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`2. SYNOPSIS
`
`Name of Sponsor
`Company:
`Salix
`Pharmaceuticals, Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Title of Study:
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`(For National Authority
`Use Only)
`
`The Relative Absorption and Disposition of 5-Aminosalicylic Acid Administered in the
`Fasting State to Healthy Human Subjects: Comparison Between 800 mg Asacol® Twice
`Daily, 800 mg Mesalamine Pellet Formulation Twice Daily. and 1600 mg Mesalamine
`Pellet Formulation Once Daily
`
`Investigators:
`
`James D. Carlson, PharmD
`
`Study Center(s):
`
`PRACS Institute. Ltd.
`4801 Amber Valley Parkway
`Fargo, ND 58104
`
`Publication
`(reference):
`
`Phase of
`Development:
`
`Study Period:
`
`Objective:
`
`No publications based on the study were available at the time of this clinical study report.
`
`December 2003 — February 2004
`
`PRIMARY OBJECTIVE:
`
`To test the hypothesis that fecal excretion of 5-
`salicylic acid (5-ASA) plus N-acetyl-
`5-aminosalicylic acid (N-Ac-5-ASA) with mesalamine
`pellets (MP) 1600 mg administered
`to that with Asacol® 800 mg
`orally (PO) once daily (QD) is non-inferior (equivalent)
`administered PO twice daily (BID).
`SECONDARY OBJECTIVES:
`of 5-ASA plus N-Ac-5-ASA with MP
`1. To test the hypothesis that fecal excretion
`800 mg BID is non-inferior (equivalent) to
`that with Asacol® 800 mg BID.
`of 5-ASA plus N-Ac-5-ASA with MP
`2. To test the hypothesis that urinary excretion
`with Asacol' 800 mg BID.
`1600 mg once daily is non-superior to that
`of 5-ASA plus N-Ac-5-ASA with MP
`3. To test the hypothesis that urinary excretion
`
`Asacol® 800 mg BID. 800 mg BID is non-superior to that with
`
`observed plasma concentration (C„.„) and the 4. To test the hypothesis that the maximum
`curve (AUC) for 5-ASA plus N-Ac-5-ASA
`area under the plasma concentration-time
`to that with Asacol® 800 mg BID. with MP 1600 mg once daily are non-superior
`
`
`AUC for 5-ASA and N-Ac-5-ASA with 5. To test the hypothesis that plasma Cm. and
`
`with Asacol® 800 mg BID. MP 800 mg BID are non-superior to that
`
`mesalamine granules, but the old Note: Mesalamine pellets are currently called
`used in the statistical output.
`terminology is used in this report because it was
`
`Confidential Information—Subject to Protective Order
`
`SALIX00378803
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`(For National Authority
`Use Only)
`
`Name of Sponsor
`Company:
`Salix
`Pharmaceuticals, Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Methodology:
`
`Number of
`Subjects:
`
`Diagnosis and Main
`Criteria for
`Inclusion:
`
`Test Product, Dose
`and Mode of
`Administration,
`Batch Number:
`
`Reference Therapy,
`Dose and Mode of
`Administration,
`Batch Number:
`
`Duration of
`Treatment:
`
`tablets) BID for 4 days
`
`This was a single-center, phase 1, open-label,
`randomized, crossover study of 3 treatments
`
`in 3 study periods that were separated by a minimum washout of 7 days. Treatments were
`administered orally as follows:
`Treatment A: (cid:9)
`800 mg Asacol® (2 x 400 mg
`800 mg MP BID for 4 days
`Treatment B: (cid:9)
`1600 mg MP (2 x 800 mg)
`Treatment C: (cid:9)
`QD for 4 days
`Participating subjects received treatments A, B,
`and C, with each being administered
`during one of the three 4-day study treatment
`periods. At the start of each treatment period,
`subjects were admitted to the evaluation unit on
`Study Day 0, at least 10 hours prior to
`dosing (Study Day 1). Subjects remained in the
`unit and were dosed with the assigned
`
`treatment for that study period on Days 1 through 4. Subjects were discharged at 7 AM on
`
`Day 5 of the treatment period, ie, 96 hours after the first dose. A washout of at least 7 days
`occurred between each 4-day treatment period.
`Plasma, urine, and feces were collected to
`
`assess relative absorption and disposition of 5-ASA and N-Ac-5-ASA. Safety assessments
`included adverse events (AEs), vital signs, physical
`examinations, and clinical laboratory
`assessments (hematology, serum chemistry and
`urinalysis).
`
`Thirty (30) subjects were randomized to obtain 24 evaluable subjects.
`
`Healthy male or female subjects between the ages of 18 and 45 years, medically normal
`with no significant abnormal findings as evaluated
`by the clinical investigator. Subjects
`the Metropolitan Height and Weight Table,
`were within ± 15% of recommended weight per
`
`and a negative alcohol (ETOH) test at had negative urine test for selected drugs of abuse
`
`non-childbearing potential or using screening and check-in, and if female, were of
`contraception specified in the protocol.
`
`•
`
`•
`
`•
`
`Treatment B: 800 mg MP BID, every 12 hours, for 4 days (8 doses), with the last pair
`of doses on the fourth day. Lot number: 0304131
`
`Treatment C: 1600 mg MP (2 x 800 mg) QD, every 24 hours, for 4 days (4 doses),
`with the last dose on the fourth day. Lot number: 0304131
`
`Treatment A: 800 mg Asacol® (2 x 400 mg tablets) BID, every 12 hours, for 4 days
`(8 doses), with the last pair of doses on the fourth day. Lot number: 417677
`
`Three 4-day treatment periods, each separated by a 7 day minimum washout period.
`
`3
`
`Confidential Information—Subject to Protective Order
`
`SALIX00378804
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`(For National Authority
`Use Only)
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`Name of Sponsor
`Company:
`Salix
`Pharmaceuticals, Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Criteria for
`Evaluation:
`
`Pharmacokinetic: All stool and urine specimens were collected during Days 1 to 4 (0 to 96 h) of each
`treatment period. Blood was drawn for determination of plasma concentrations on Day 4
`predose and at 1, 2, 3. 4, 6, 8, 10, 12, 16, 20 and 24 hours after dosing. Concentrations of
`5-ASA and its metabolite N-Ac-5-ASA in feces (soluble, total, and intact), plasma, and
`urine were used to determine the following pharmacokinetic parameters for each treatment:
`• Cumulative amount of 5-ASA plus N-Ac-5-ASA excreted in the feces for the entire
`study period (0 to 96 h).
`• Cumulative amount of 5-ASA plus N-Ac-5-ASA excreted in the urine for the entire
`study period (0 to 96 h).
`• Day 4 maximum plasma concentration (Cmax, jtmoUL)
`• Day 4 area under the plasma concentration-time curve from time zero to 24 hours
`(AUCG_21, jtmol*h/L) for once daily dosing.
`• Day 4 area under the plasma concentration-time curve over the sampling interval
`calculated by linear trapezoidal rule for BID dosing: AUCc = AUC0_12 X (1 +
`(AUC12-24/AUCo-12) (jtmol*h/L).
`• Day 4 time of maximum plasma concentration (Tn. h).
`
`Safety criteria included adverse events, serious adverse events (SAEs), clinical laboratory
`
`parameters (hematology, clinical chemistry, urinalysis), vital signs, and results of physical
`examination
`
`Safety:
`
`Statistical Methods:
`
`Safety:
`
`Results:
`
`Demographics and
`Baseline
`Characteristics:
`
`minimum and maximum values, and the
`Descriptive statistics (mean ± SD, median with
`number and percentage of subjects) were used
`to summarize subject demographic and
`safety variables.
`
`Thirty subjects were randomized in the study
`and 28 completed all 3 treatment periods.
`One subject discontinued due to AEs and one
`subject was discontinued due to a protocol
`violation. Subjects were predominately male (83%)
`and Caucasian (73%). Mean subject
`was 77 kg (54-100 kg), and mean height was
`age was 27 years (19-45 years), mean weight
`
`met all eligibility criteria for enrollment. 176 cm (155-188 cm). Each of the 30 subjects
`
`4
`
`Confidential Information—Subject to Protective Order
`
`SALIX00378805
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`(For National Authority
`Use Only)
`
`Name of Sponsor
`Company:
`Salix
`Pharmaceuticals, Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Pharmacokinetic
`Results:
`
`The Pharmacokinctic Evaluable populations i icluded 27 subjects for fecal analysis,
`21 subjects for urine analysis, and 28 subjects for plasma analysis. Due to the combination
`of identified drug wasting via fecal excreted tablets and high variability of the data from
`Asacol'', no statistical comparisons with Treatment A could be made with regard to the
`primary and secondary objectives of the study. However, comparisons between MP BID
`and MP QD dosing can be made.
`Plasmsa pharmacokinetic parameters collected for Day 4 are presented below.
`Plasma Pharmacokinetic Parameters (Da 4)
`Treatment A
`Treatment B
`Treatment C
`Asacol 800 mg
`MP 800 mg
`MP 1600 mg
`BID
`BID
`QD
`
`Ratio C/Ba
`(90% CI)
`
`1.82 ± 0.71
`3.61 f 1.23
`
`3.04 ± 1.67
`4.50 f 1.82
`
`153 (113, 208)
`118 (98, 143)
`
`C. (cid:9) (pg/mL)r4
`5-ASA
`1.06 ± 1.37
`N-Ac-5-
`2.34 ± 1.80
`ASA
`AUC (pg*h/mL)d
`5-ASA
`8.34 ± 7.50
`N-Ac-5-
`ASA
`1.1112X (1 )
`3.0 (2.0, 16.0)
`16.0 (0, 24.0)
`16.0 (0, 24.0)e
`5-ASA
`N-Ac-5-
`3.0 (2.0, 24.0)
`16.0 (0, 24.0)
`16.0 (0, 24.0)
`ASA
`a Calculated from geometric means of log transformed data.
`b Cmax and AUC values were converted from µmol/L and innol*h/L to pg/mL
`and µg*h/mL by multiplying by 0.153.
`CIllaX and AUC values were converted from pmol/L and timolsh/L to pg/mL
`and µg*h/mL by multiplying by 0.195.
`d AUC values for Treatments A and B are AUC c and for Treatment C arc
`AUC0_24. AUCc = AUC0.12 X (1 + (AUC12-24/AUCo-12).
`e Median (range).
`
`14.84 ± 5.50
`
`14.76 ± 6.49
`
`96 (76, 121)
`
`30.72 ± 22.25
`
`46.37 ± 15.43
`
`45.85 ± 19.71
`
`93 (78, 112)
`
`-
`
`Based on the fecal and urine data collected up to 24 hours post-dosing on Day 4, the study
`showed that the mean cumulative fecal excretion of 5-ASA plus N-Ac-5-ASA was
`comparable between the once daily (1600 mg QD) and twice daily (800 mg BID) dosing
`regimens for MP. The mean cumulative urinary excretion of 5-ASA plus N-Ac-5-ASA was
`also comparable between the QD and BID MP regimens.
`
`Confidential Information-Subject to Protective Order
`
`SALIX00378806
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`Name of Sponsor
`Company:
`Salix
`Pharmaceuticals, Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Safety Results:
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`(For National Authority
`Use Only)
`
`• No SAEs or deaths were reported in this study.
`• All AEs were mild or moderate in severity and resolved without sequelae.
`• One subject (Treatment Group 1: ABC randomization) discontinued from the study
`because of mild AEs (oral pain, sinus pain, face swelling) after receiving 1 dose of MP
`QD (Treatment C) and after having completed a 4-day regimen of MP 800 mg BID
`(Treatment B) and Asacol® (Treatment A). The investigator considered these AEs to be
`not related to study drug and the events resolved within 1 week.
`• AEs were more common with MP at 800 mg BID (n = 6 subjects, 20.0%) and 1600 mg
`QD (n = 5, 17.2%) compared to 800 mg Asacol® QD (n = 2, 6.7%).
`• Headache was the most commonly reported AE, occurring in 3 subjects with MP QD
`and 2 with MP BID; other AEs reported in > 1 subject included flatulence (2 with
`Asacol BID), and erythema (1 each with MP BID and MP QD).
`• AEs related to MP in this study (headache, flatulence, nausea, hunger) were consistent
`with those previously observed with mesalamine administration.
`• No clinically significant changes were reported in senun chemistry, hematology, or
`urinalysis. Sporadic decreases in creatinine clearance were observed in subjects after
`administration of all 3 study treatments; however, these changes followed no pattern
`and were believed to be secondary to variability in urine volumes.
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378807
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`(For National Authority
`Use Only)
`
`Name of Sponsor
`Company:
`Salix
`Pharmaceuticals. Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Discussion and
`Conclusions:
`
`Date of Report:
`
`Mesalamine pellets were safe and well tolerated in healthy adult volunteers when
`administered orally once daily (1600 mg QD) and twice daily (800 mg BID). All AEs
`reported in this study were consistent with the known pharmacologic profile of 5-ASA.
`
`The extent of systemic absorption of 5-ASA and N-Ac-5-ASA at presumed steady state as
`measured by AUC was similar for both MP regimens. Steady state plasma concentrations
`of 5-ASA and N-Ac-5-ASA as measured by C.., were higher following MP administered
`QD compared to BID. Comparisons between Asacol® and MP regimens were not possible
`because of the variability in systemic exposure to 5 ASA and N-Ac-5-ASA following
`Asacol® dosing. (Note: Plasma concentrations were assumed to be at steady state because
`the T112 values for 5-ASA and N-Ac-5-ASA in MPPK1002 [a Salix food-effect study with
`MP] after a 1600 mg dose to fasted subjects were 5.49 hours and 10.05 hours,
`respectively.)
`
`The time to maximum drug concentrations was shorter for MP administered QD than BID
`for 5-ASA (mean of 3.96 vs. 11.00 hours, respectively) and for N-Ac-5-ASA (mean of 5.21
`vs. 11.68 hours, respectively).
`
`The fecal data were highly variable and the analysis methods were flawed, but because the
`methods were similar throughout the study some general comparisons can be made
`between the MP groups. The cumulative fecal and urinary excretion of 5-ASA and N-Ac-5-
`ASA were comparable between MP administered once daily (1600 mg QD) and twice daily
`(800 mg BID); however, these data are based on collection of data limited to 24 hours post
`dosing on Day 4. Treatment comparisons between Treatment A (Asacol®) and the MP
`regimens were limited by the observation of intact and partially intact Asacol® tablets in
`fecal samples of approximately 50% of subjects who were administered Treatment A
`(Asacol®) and the inability of the extraction method to differentiate between released and
`total mesalamine. It is not known how the limitations of the extraction method impacted
`the fecal analysis results of Treatments B and C.
`01 October 2007
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378808
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`3. TABLE OF CONTENTS
`
`1. TITLE PAGE (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`
`
`2.
`
`SYNOPSIS 000000990000000000990000000090990000000000•9000.10000099110000•00001,9000000080099•000060000990000001.0099000000000•990000000•009 (cid:9) 2
`
`3.
`
`TABLE OF CONTENTS ai••••••006600••••• 66666 1.0••••••006600.11111100006600•41111100006600.1111100006.100•4111110000660.1•111.0006600••••••68
`
`4. LIST OF ABBREVIATIONS
`
`66666 (cid:9)
`1-6
`5. ETHICS (cid:9)
`5.1. (cid:9)
`Institutional Review Board/Independent Ethics Committee...................................16
`5.2. (cid:9)
`16
`Ethical Conduct of the Study (cid:9)
`Subject Information and Consent 66666 (cid:9)
`16
`5.3. (cid:9)
`6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE (cid:9)
`17
`
`(cid:9) (cid:9)
`
`20
`20
`20
`
`8. STUDY OBJECTIVES (cid:9)
`8.1. (cid:9)
`Primary Objective.................... ..... (cid:9)
`8.2. Secondary
`.....
`9. INVESTIGATIONAL PLAN
`21
`9.1. (cid:9)
`
`Study Design (cid:9)
`9.2. (cid:9)
`
`Discussion of Study Design (cid:9)
`21
`22
`
`9.3. (cid:9)
`Selection of Study Population (cid:9)
`22
`9.3.1. (cid:9)
`Inclusion Criteria (cid:9)
`
`23
`9.3.2. (cid:9)
`Exclusion Criteria (cid:9)
`
`24
`9.3.3. (cid:9)
`
`Removal of Subjects from Therapy or Assessment (cid:9)
`24
`9.4. (cid:9)
`Treatments (cid:9)
`
`24
`9.4.1. (cid:9)
`Treatments Administered (cid:9)
`
`24
`9.4.2. (cid:9)
`
`Identity of Investigational Product (cid:9)
`25
`9.4.3. (cid:9)
`
`Method of Assigning Subjects to Treatment Groups (cid:9)
`25
`9.4.4. (cid:9)
`
`Selection of Doses in the Study (cid:9)
`25
`9.4.5. (cid:9)
`
`Selection and Timing of Dose for Each Subject (cid:9)
`25
`9.4.6. (cid:9)
`Blinding (cid:9)
`
`25
`9.4.7. (cid:9)
`
`Prior and Concomitant Therapy (cid:9)
`26
`9.4.8. (cid:9)
`Treatment Compliance (cid:9)
`
`9.5. (cid:9)
`Pharmacokinetic and Safety Variables..................................................... ............... ..26
`9.5.1. (cid:9)
`26
`Pharmacokinetic and Safety Measurements Assessed and Schedule (cid:9)
`
`9.5.2. (cid:9)
`29
`Pharmacokinetic Assessments (cid:9)
`
`9.5.2.1. (cid:9)
`29
`Processing and Assay of Biological Samples (cid:9)
`
`9.5.3. (cid:9)
`29
`Bioa.nalytical Methods (cid:9)
`
`9.5.3.1. (cid:9)
`Fecal Pharmacokinetic Parameters (cid:9)
`29
`
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378809
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
`
`

`
`........ (cid:9)
`
`........ (cid:9)
`
`........ (cid:9)
`
`........
`
`........ (cid:9)
`
`
`
`
`
`
`
`
`
`
`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`........ (cid:9)
`
`......... (cid:9)
`
`........ (cid:9)
`
`........ (cid:9)
`
`........ (cid:9)
`
`30
`Plasma Pharmacokinetic Parameters (cid:9)
`9.5.3.2. (cid:9)
`
`9.5.3.3. (cid:9) Urine Pharmacokinetic Parameters (cid:9)
`31
`
`32
`9.5.4. (cid:9)
`
`Safety Assessments (cid:9)
`9.5.4.1. (cid:9) Adverse Events (cid:9)
`33
`
`9.5.4.2. (cid:9)
`Physical (cid:9) Examination (cid:9)
`....... ......33
`........
`9.5.4.3. (cid:9) Vital Signs (cid:9)
`33
`
`9.5.4.4. (cid:9) Clinical Laboratory Tests (cid:9)
`33
`
`34
`9.5.4.5. (cid:9) Medical History (cid:9)
`
`9.6. (cid:9)
`Data Quality Assurance........... ..... ................................................. ...... . ........... ......... ..34
`
`34
`Statistical Methods and Determination of Sample Size (cid:9)
`9.7. (cid:9)
`Statistical and Analytical Plans (cid:9)
`
`34
`9.7.1. (cid:9)
`9.7.1.1. (cid:9) General (cid:9) Considerations...... ........ (cid:9)
`........ 34
`9.7.1.2. (cid:9) Analysis Sets (cid:9)
`35
`9.7.1.3. (cid:9) Disposition of Subjects (cid:9)
`35
`9.7.1.4. (cid:9) Demographic and Baseline Data (cid:9)
`35
`9.7.1.5. (cid:9) Pharmacokinetic Analysis (cid:9)
`35
`9.7.1.6. (cid:9)
`Safety Endpoints (cid:9)
`37
`9.7.2. (cid:9)
`Sample Size Justification and Planned Power (cid:9)
`37
`9.8. (cid:9)
`Changes in the Conduct of the Study or Planned Analyses (cid:9)
`37
`9.8.1. (cid:9)
`Changes in the Conduct of the Study (cid:9)
`37
`9.8.2. (cid:9)
`Changes in Planned Analyses (cid:9)
`38
`10. STUDY
`39
`10.1. (cid:9) Disposition of Subjects............. ..... (cid:9)
`10.2. (cid:9) Protocol Deviations ............... ........ . ...... .......................................... ............................. (cid:9) 39
`10.2.1. Enrollment Exceptions (cid:9)
`39
`10.2.2. Deviations During Conduct of the Study (cid:9)
`39
`10.2.3. Concomitant Medications (cid:9)
`40
`11. PHARMACOKINETIC AND STATISTICAL ANALYSIS (cid:9)
`41
`41
`11.1. Data Sets Analyzed .................. ..... (cid:9)
`11.2. Demographics and Other Baseline Characteristics.................... ..... ........ .............. (cid:9) 41
`11.2.1. (cid:9)
`41
`Subject Demographics (cid:9)
`11.2.2. (cid:9)
`42
`Subject Medi cal Hi story (cid:9)
`11.2.3. (cid:9)
`43
`Prior Medications (cid:9)
`11.3. (cid:9) Measurements of Treatment Compliance .................................................................43
`11.4. (cid:9) Pharmacokinetic Results......... ..... ................................................. ..... ............. ......... ...43
`11.4.1. (cid:9)
`43
`Pharmacokinetic Analysis (cid:9)
`
`11 4 1.1. Mixed Model ANOVA for Pharmacokinetic Parameters (cid:9)
`43
`
`11 4 1.2. Fecal Excretion (cid:9)
`43
`
`11 4.1.3. Urinary Excretion (cid:9)
`44
`
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378810
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 9
`
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`........ (cid:9)
`
`........ (cid:9)
`
`I I .4.1.4. (cid:9) Plasma Concentrations ........ ........ (cid:9)
`11.4.2. (cid:9)
`Statistical and Analytical Issues (cid:9)
`11.4.3. (cid:9)
`Tabulation of Individual Response Data (cid:9)
`11.4.4. Drug Dose, Drug Concentration, and Relationship to Response (cid:9)
`11.4.5. Drug-Drug and Drug-Disease Interactions (cid:9)
`11.4.6. (cid:9)
`By-Subject Displays (cid:9)
`11.4.7. (cid:9)
`Pharmacokinetic and Statistical Conclusions (cid:9)
`
`........ (cid:9)
`
`........ (cid:9)
`
`........
`
`45
`47
`47
`48
`48
`48
`48
`
`50
`12. SAFETY EVALUATION (cid:9)
`50
`12.1. Extent of Exposure (cid:9)
`50
`12.2. Adverse Events (cid:9)
`50
`12.2.1. Brief Summary of Adverse Events (cid:9)
`12.2.2. Display of Adverse Events (cid:9)
`51
`51
`12.2.3. Analysis of Adverse Events (cid:9)
`53
`12.2.4. Listing of Adverse Events by Subject (cid:9)
`12.3. Deaths, Other Serious Adverse Events, and Other Significant Adverse Events (cid:9) 53
`12.3.1. (cid:9)
`Listing of Deaths, Other Serious Adverse Events, and Other Significant Adverse
`Events (cid:9)
`53
`12.3.1.1. Deaths (cid:9)
`53
`12.3.1.2. Other Serious Adverse Events (cid:9)
`53
`12.3.1.3. Other Significant Adverse Events (cid:9)
`54
`12.3.2. (cid:9) Narratives of Deaths, Other Serious Adverse Events, and Other Significant
`Adverse Events (cid:9)
`12.3.3. (cid:9) Analysis and Discussion of Deaths, Other Serious Adverse Events, and Other
` 54
`Significant Adverse Events (cid:9)
` 54
`12.4. (cid:9) Clinical Laboratory Evaluation (cid:9)
` 54
`12.4.1. (cid:9)
`Listing of Individual Laboratory Values (cid:9)
` 54
`12.4.2. (cid:9)
`Evaluation of Each Laboratory Parameter (cid:9)
` 54
`12.4.2.1. Mean Laboratory Values Over Time (cid:9)
` 55
`12.4.2.2. Individual Subject Changes (cid:9)
` 55
`12.4.2.3. Individual Clinically Significant Laboratory Abnormalities (cid:9)
`12.5. Vital Signs, Physical Findings, and Other Observations Related to Safety ...........56
`
` 54
`
`13. DISCUSSION AND OVERALL CONCLUSIONS (cid:9)
`13.1. Discussion (cid:9)
`
`57
`57
`
`14. TABLES AND FIGURES REFERRED TO BUT NOT INCLUDED IN THE TEXT ...59
`14.1. Demographic Data Summary Figures and
`14.2. Pharmacokinetic Data Summary Figures and Tables (cid:9)
`14.3. Safety Data Summary Figures and Tables (cid:9)
`
`64
`291
`
`10
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378811
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 10
`
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`15. REFERENCES................ ..... ..................................................................................................16
`16. APPENDICES
`16.1. Study Information
`16.1.1. Protocol and. Protocol Amendments
`16.1.2. Sample Case Report Forms
`16.1.3. IRB/IEC and Approved Information and Consent Forms
`16.1.3.1. Institutional Review Board Members
`16.1.3.2. Approved Informed Consent Form
`16.1.4. List and CVs of Investigators and Other Important Participants
`16.1.5. (cid:9)
`Signature of Principal or Coordinating Investigator or Sponsor's Responsible
`Medical Officer
`16.1.6. List of Subjects Receiving Each Batch of Study Drug
`161.7. Randomization Scheme and Codes
`16.1.8. (cid:9) Audit Certificates
`16.1.9. Documentation of Statistical Methods
`16.1.9.1. Data Analysis Plan
`16.1.9.2. Bioanalytical Report
`16.1.9.3. Analytical Report No. 052-04004D
`16.1.9.4. Analytical Report No. 052-04005D
`16.1.9.5. Analytical Report No. 052-04006D
`16.1.9.6. Method Validation Report No. 052-04001V
`16.1.9.7. Method Validation Report No. 052-03002V
`16.1.9.8. Method Validation Report No. 052-03003V
`16.1.10. Laboratory Standardization and Quality Assurance
`16.1.11. Publications Based on This Study
`16.1.12. Important Publications Referenced in the Report
`16.2. Subject Data Listings
`16.2.1. (cid:9)
`Subject Characteristic Listings
`16.2.2. Pharmacolcinetic Evaluation Listings
`16.2.3. (cid:9)
`Safety Listings
`16.3. Case Report Forms
`16.4. Individual Subject Data Listings
`
`11
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378812
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 11
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`LIST OF IN-TEXT TABLES
`
`........ (cid:9)
`
`........ (cid:9)
`
`........ (cid:9)
`
`........ (cid:9)
`
`........
`
`Table 1. (cid:9)
`......... (cid:9)
`Study Administration Structure ...... (cid:9)
`Table 2. Schedule of Assessments and Procedures (cid:9)
`Table 3. Assessments and Procedures for Study Period 3 or Early Discontinuation (cid:9)
`Table 4. Subject Disposition (cid:9)
`Table 5. Subject Demographics and Baseline Characteristics (cid:9)
`Table 6. Plasma Pharmacokinetic Parameters for 5-ASA and N-Ac-5-ASA with Different
`Treatments (Day 4) (Mean ± SD, in umol) (cid:9)
`Table 7. Plasma Pharmacokinetic Parameters for 5-ASA and N-Ac-5-ASA with Different
`47
`Treatments (Day 4) (Mean ± SD, in pg) (cid:9)
`........ .....51
`........ (cid:9)
`........ (cid:9)
`Summary of Adverse Events (cid:9) Safety Population...... ........ (cid:9)
`Table 8. (cid:9)
`Table 9. Summary of All Treatment-Emergent Adverse Events by System Organ Class and
`Treatment Group (cid:9)
`Table 10. Summary of Adverse Events Related to Treatment with Asacol® 800 mg BID, MP
`800 mg BID or 1600 mg QD (cid:9)
`
`27
`28
`39
`42
`
`46
`
`52
`
`53
`
`12
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378813
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 12
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`4. LIST OF ABBREVIATIONS
`
`Abbreviation (cid:9)
`
`Aefe
`
`IAefe
`
`IAefc(both)
`
`%LAere
`
`°/OIAefe(both)
`
`AeUr
`
`1Aeur
`
`°/01',Aeur (cid:9)
`
`LAeur(bott)
`
`%ZAeur(both)
`
`AE (cid:9)
`ALT/SGPT (cid:9)
`ANOVA (cid:9)
`5-ASA (cid:9)
`AST/SGOT (cid:9)
`
`AUCo-12
`
`AUC0-24
`
`AUC A
`
`Definition
`Amount of analyte excreted in the feces from time zero to 24 hrs
`for each study day
`Cumulative amount of analyte excreted in the feces for the entire
`study period (Day 1 through Day 4)
`Cumulative amount of both analytes (5-ASA plus N-Ac-5ASA)
`excreted in the feces for the entire study period
`Percent of dose excreted as each analyte in the feces for the
`entire study period
`Percent of dose excreted as the cumulative amount of both
`analytes (5-ASA plus N-Ac-5ASA) in the feces for the entire
`study period
`Cumulative amount of analyte excreted in the urine from time
`zero to time 24 hours for each study day
`Cumulative amount of analyte excreted in the urine from time
`zero to time 96 hours
`Percent of dose excreted of each analyte in the urine for the
`entire study period (0-96 h)
`The cumulative amount of both analytes (5-ASA plus
`N-Ac-5ASA) excreted in the urine for the entire study period (0-
`96 h)
`The percent of dose of the total cumulative amount of both
`analytes (5-ASA plus N-Ac-5ASA) excreted in the urine
`Adverse event
`Alanine aminotransferase
`Analysis of variance
`5-Aminosalicylic acid (mesalamine)
`Aspartate aminotransferase
`Area under the plasma concentration-time curve from time 0 to
`12 hours
`
`Area under the plasma concentration-time curve from time 0 to
`24 hours
`Area under the plasma concentration time curve calculated for
`samples at Hours 12, 16, 20 and 24 by linear trapezoidal rule for
`BID dosing.
`
`13
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378814
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 13
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`Abbreviation (cid:9)
`AUC B
`
`AUC c (cid:9)
`
`BID (cid:9)
`BUN (cid:9)
`C (cid:9)
`CFR (cid:9)
`CL (cid:9)
`Cmax (cid:9)
`
`Cmax/Cmin (cid:9)
`
`Cmax/Cave (cid:9)
`CRF (cid:9)
`CV (cid:9)
`ETOH (cid:9)
`FDA (cid:9)
`GCP (cid:9)
`HIV (cid:9)
`IB (cid:9)
`IBD (cid:9)
`ICH (cid:9)
`IRE (cid:9)
`ITT (cid:9)
`IUD (cid:9)
`kg (cid:9)
`MedDRA (cid:9)
`mg (cid:9)
`mL (cid:9)
`mmol (cid:9)
`MP (cid:9)
`N-Ac-5-ASA (cid:9)
`ng (cid:9)
`OTC (cid:9)
`
`Definition
`Area under the plasma concentration time curve over the
`sampling interval calculated for samples at Hours 0, 4, 8 and 12
`by linear trapezoidal rule for BID dosing.
`Area under the plasma concentration time curve over the
`sampling interval calculated by linear trapezoidal rule for BID
`dosing: AUCc = AUC0_12 X (1 + (AUCA/AUCB).
`Two times a day
`Blood urea nitrogen
`Celsius
`U.S. Code of Federal Regulations
`Clearance
`Maximum plasma concentration
`Peak-to-trough plasma concentration ratio.
`Peak-to-average plasma concentration ratio.
`Case Report Forni
`Curriculum Vitae or Coefficient of variation
`Ethyl alcohol
`Food and Drug Administration
`Good Clinical Practices
`Human immunodeficiency virus
`Investigator's Brochure
`Inflammatory bowel disease
`International Conference on Harmonization
`Institutional Review Board
`Intention-to-treat
`Intrauterine device
`Kilogram
`Medical Dictionary for Drug Regulatory Affairs
`Milligram
`Milliliter
`Millimoles
`Mesalamine Pellets
`N-acetyl-5-aminosalicylic acid (acetyl-mesalamine)
`Nanogram
`Over the counter
`
`14
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378815
`
`Dr. Falk Ex. 2045
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 14
`
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1001 Clinical Study Report
`Final: 01 October 2007
`
`Abbreviation (cid:9)
`PL/SQL
`PO
`QD (cid:9)
`RBC (cid:9)
`SAE (cid:9)
`SEM (cid:9)
`SD (cid:9)
`
`TID (cid:9)
`Ti (cid:9)
`
`Tiag
`
`TmaX
`UC (cid:9)
`ULN (cid:9)
`
`WBC (cid:9)
`WMA (cid:9)
`
`Definition
`Oracle2® Procedure Language / Structured Query Language
`Orally
`Once daily
`Red blood cells
`Serious adverse event
`Standard error of the mean
`Standard deviation
`Terminal exponential phase half life calculated as 0.693az
`Three times a day
`Time of last measurable plasma concentration
`Lag time for absorption
`Time to maximum plasma concentration
`Ulcerative colitis
`Upper limit of normal
`Urinary volume
`White blood cells
`World Medical Association
`
`15
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00378816
`
`Dr. Falk Ex.