Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL, (cid:9)
`
`NIPPK1002 Clinical Study Report
`Final: 01 October 2007
`
`i a L
`
`1't (cid:9)
`
`crt.sa't r t , INC,
`
`5 1
`
`;,:. {
`
`Salix Pharmaceuticals, Inc.
`
`WO
`
`The Effect of a High®Fat Meal on the Absorption of a Single,
`1600 mg Oral Dose of Mesalamine (5-aminosalicylic acid)
`Administered as a Pellet Formulation
`
`Name of Test/Investigational Drug:
`Indication Studied:
`Phase of Study:
`Protocol Number:
`
`Mesalamine
`Not applicable; pharmacokinetic study
`
`MPPK 1002
`
`Study Initiation Date:
`Study Completion Date:
`Date of Study Report:
`
`Study Sponsor: (cid:9)
`
`Name of Sponsor Signatory: (cid:9)
`
`06 January 2004 (first consent signed)
`06 February 2004
`01 October 2007
`
`Salix Pharmaceuticals, Inc
`1700 Perimeter Park Drive
`Morrisville, North Carolina, USA 27560
`Tel: (919) 862-1000; 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.
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00373973
`
`Dr. Falk Ex. 2029
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`1MIPPK1002 Clinical Study Report
`Final: 01 October 2007
`
`Name of Sponsor
`Company:
`Salix Pharmaceuticals, Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Title of Study:
`
`Investigator(s):
`
`Study Center(s):
`
`(For VationalAuthority
`Use Only)
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`The Effect of a High-Fat Meal on the Absorption of a Single, 1600 mg Oral Dose of
`Mesalamine (5-aminosalicylic acid) Administered as a Pellet Formulation
`
`James D. Carlson, PharmD
`
`PRACS Institute, Ltd.
`4801 Amber Valley Parkway
`Fargo, ND 58104
`
`Publication (reference):
`
`No publications based on the study were available at the time of this clinical study
`report.
`
`Phase of Development:
`
`Phase I
`
`Study Period
`
`Objectives:
`
`06 January 2004 (first consent signed) — 06 February 2004
`
`PRIMARY OBJECTIVES:
`The primary objective of the study was to compare the pharmacokinetics and the
`urinary and fecal excretion of 5-aniinosallcylic acid (5-ASA, mesalamine) and
`N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA, acetyl-mesalamine) from a single
`1600-mg oral dose of mesalamine pellets (MP) administered during fasting and after a
`high-fat meal. Results from this study were used to demonstrate the extent to which
`systemic and colonic exposure to 5-ASA and N-Ac-5-ASA may be altered by a meal.
`
`SECONDARY OBJECTIVES:
`1. To test the hypothesis that fecal excretion of intact drug (5-ASA) following NIP
`1600 mg administered with a meal is significantly greater than when
`administered during fasting.
`2. To test the hypothesis that urinary excretion of 5-ASA plus N-Ac-5-ASA
`following NIP 1600 mg orally administered with a meal is significantly less than
`when administered during fasting.
`3. To test the hypothesis that the maximum observed plasma concentration (C,,,,)
`and the area under the plasma concentration-time curve (AUC) for 5-ASA plus
`N-Ac-S -ASA following NIP 1600-mg orally administered with a meal is
`significantly less than when administered during fasting.
`
`Note: Mesalamine pellets are currently called mesalamine granules, but the older
`term is retained for this study because it was used in the statistical output.
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00373974
`
`Dr. Falk Ex. 2029
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`

`
`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
`Methodology:
`
`A/IPPK1002 Clinical Study Report
`Final: 01 October 2007
`
`(For !National Authority
`Use Only)
`
`A phase 1, open-label, randomized, balanced, two-treatment, two-period, two-
`sequence, crossover study of a single dose mesalamine pellet formulation (1600 mg,
`2 x 800 mg) administered orally following an overnight fast and following ingestion
`of a high-fat meal (breakfast). Study periods (4 days) were separated by a minimum
`of 7 days. Plasma, urine, and feces were collected to assess the effect of a high-fat
`meal on the pharmacokinetics of 5-ASA and N-Ac-5-ASA.
`
`Number of Subjects:
`
`Thirty (30) subjects were randomized to obtain 24 evaluable subjects.
`
`Diagnosis and main
`criteria for inclusion:
`
`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 were within ±15% of recommended weight per the Metropolitan Height and
`Weight Table, had negative urine test for selected drugs of abuse and a negative
`alcohol (ETOH) at screening and check-in, and if female, were of non-childbearing
`potential or using contraception specified in protocol.
`
`Test treatment, dose and Single oral dose (1600 mg, 2 x 800 mg) of MP formulation following consumption of
`mode of administration,
`a high-fat meal (breakfast) (Lot number: 0304131).
`batch number:
`
`Reference treatment,
`dose and mode of
`administration, batch
`number:
`
`Single oral dose (1600 mg, 2 x 800 mg) MP formulation following an overnight fast
`(Lot number: 0304131).
`
`Duration of treatment:
`
`Single dose on Day 1 of each of the 2 study periods.
`
`Criteria for evaluation:
`
`Pharmacokinetic:
`
`Safety:
`
`Biopharmaceutical/Phar macokinetic:
`• (cid:9) Cumulative fecal excretion of 5-ASA and N-Ac-5-ASA for the 96-hour (4 day)
`study period.
`• (cid:9) Cumulative urinary excretion of 5-ASA and N-Ac-5-ASA for the 96-hour (4 day)
`study period.
`® (cid:9) Time to maximum observed plasma concentration (T max ), Cma„ the area under the
`plasma concentration versus time curve from time zero (0) to the last measurable
`time point (AUCa1,, ), and the area under the plasma concentration versus time
`curve extrapolated from time zero (0) to time = infinity (AUC0_i f) for 5-ASA and
`N-Ac-5-ASA.
`
`Adverse events (AEs), deaths, serious adverse events (SAEs), and other significant
`AEs; clinical laboratory parameters (hematology, clinical chemistry, urinalysis); vital
`signs; results of physical examination and creatinine clearance.
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00373975
`
`Dr. Falk Ex. 2029
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`Salix Pharmaceuticals, Inc
`
`CONFIDENTIAL (cid:9)
`
`I\/IPPK1002 Clinical Study Report
`Final: 01 October 2007
`
`Name of Sponsor
`Company:
`Salix Pharmaceuticals, Inc.
`Name of Finished
`Product:
`Mesalamine pellets
`
`Name of Active
`Ingredient:
`5-aminosalicylic acid
`Statistical methods:
`
`(ForArationalAuthority
`Use Only)
`
`Individual Study Table
`Referring to Part
`of the Dossier
`
`Volume:
`
`Page:
`
`Analysis of variance models with treatment sequence, study period, treatment fixed,
`and subject within sequence random were used to analyze the log-transformed plasma
`5-ASA and N-Ac-S-ASA C,,, and AUC of and the untransformed total cumulative
`amount (0 to 96 hours) of both analytes excreted in the feces [EAe f. (both)] and urine
`[EAe, (both)]. Based on this model, statistical significance tests for the fasted/fed
`contrast, 95% confidence intervals about the treatment least-squares means, and 90%
`confidence intervals about treatment mean differences were reported.
`
`Confidence intervals around treatment least-squares means of log-transformed
`parameters were back-transformed and reported as intervals around treatment
`geometric means. Confidence intervals around mean differences of log-transformed
`parameters were reported as percent geometric mean ratios. Ratios were calculated as
`[100% * exp(x)], where x was the estimated mean difference or the lower or upper
`confidence limit for the mean difference. Confidence intervals around mean
`differences of untransformed parameters were reported as percent mean ratios.
`Equivalence was declared when lower and upper bounds of the 90% confidence
`interval were between 80% and 125% (for log-transformed parameters), or between
`80 and 120% for untransformed parameters.
`Plasma Tm,x was compared between treatments based upon individual subject
`differences using a signed rank test to test the hypothesis that the median difference
`of fed minus fasted was zero; a nonparametric and symmetric 90% confidence
`interval for the median difference was also calculated.
`
`Results:
`
`Demographics and
`Baseline
`Characteristics:
`
`A total of 30 subjects were enrolled and completed the study. Twenty-three subjects
`(76.7%) were male and 7 subjects (23,3%) were female. The mean age, weight, and
`height were 23.6 years (range 18 to 43 years), 72.4 kg (55.4 kg to 98.1 kg), and
`176.0 cm (165.1 cm to 190.5 cm), respectively.
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00373976
`
`Dr. Falk Ex. 2029
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1002 Clinical Study Report
`Final: 01 October 2007
`
`Name of Sponsor (cid:9)
`Company: (cid:9)
`Salix Pharmaceuticals, Inc.
`Name of Finished
`Product: (cid:9)
`Mesalamine pellets
`
`Name of Active
`Ingredient:
`ainosalicylic acid
`Pharmacokinetic (cid:9)
`Results:
`
`(For National Authority
`Use Only)
`
`Individual Study Table (cid:9)
`Referring to Part (cid:9)
`of the Dossier
`
`Volume:
`
`Paue:
`
`The following tables summarize the pharmacokinetic results.
`
`Plasma Pharmacnlrinetir Parameters (Mean + S.T).l and 90 0/n CT'
`Fasted
`Fed
`Fed/Fasted
`N =30
`N = 30
`Ratio (cid:9)
`I 90% CI
`
`Parameter
`Cmac ( (cid:9) mL)
`2.56 ± l .45b
`5-ASA
`3.72 + 1.85°
`N-Ac-5-ASA
`*h/rL)
`AUCo-hr( (cid:9)
`12.98 + 6.09
`5-ASA
`44.91 + 18.47°
`N-Ac-5-ASA
`T5,,,. (cid:9) h
`4.00 (3.00, 8,00)d
`8.00 (3.00, 20.00)
`5-ASA
`N-Ac-5-ASA
`6.00 (2.00, 16.00)
`8.00 (3.00, 24.00)
`Ratios and Cis calculated from geometric means of log transformed results.
`C,„a„ and AUC values were converted from pmoUL and µniol*h/L to pg/mL and pg*h/mL by
`multiplying by 0.153.
`C,,,,,,, and AUC values were converted from lunolfL and pmol*h/L to pg/nL and pg*hhnL by
`multiplying by 0.195.
`n Median (range).
`
`2.51 ± 1.27
`3.63 ± 1.38
`
`13.76 + 5.70
`43.42 + 23.56
`
`104
`103
`
`111
`95
`
`-
`-
`
`87, 125
`90, 117
`
`96, 128
`84, 108
`
`-
`-
`
`Fecal Recovery (Mean + SDl and 90% C.T.
`Fasted
`Fed
`N=30
`N=30
`(mmol)
`(mmol)
`1.27 + 0.75
`1.80 ± 1.07
`1.60 + 0.63
`1.87 + 0.97
`3,40+1,32
`3.13+1.34
`
`Component
`5-ASA
`N-Ac-5-ASA
`5-ASA plus N-
`Ac-5-ASA
`
`TJrinary Recovery (Mean +ST)1 and 90% C.T.
`Fasted
`Fed
`N=30
`N=30
`(mmol)
`(mmol)
`0.20 + 0.18
`0.26 + 0.23
`3.10± 1.00
`3.08± 1.22
`3.34± 1.36
`
`Component
`5-ASA
`N-Ac-5-ASA
`5-ASA plus N-
`Ac-5-ASA
`
`330± 1.10
`
`Fed/Fasted
`90% CI
`Ratio
`70
`56, 85
`116
`103, 129
`92
`83,101
`
`Fed/Fasted
`90% CI
`Ratio
`95, 159
`127
`100
`87, 112
`101
`88, 115
`
`5
`
`Confidential Information-Subject to Protective Order (cid:9)
`
`SALIX00373977
`
`Dr. Falk Ex. 2029
`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:
`
`IVIPPK1002 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
`Pharmacokinetic
`Results (cont'd):
`
`Safety Results:
`
`Conclusions:
`
`As expected, there was a significantly prolonged Tm,,z for both 5-ASA and
`N-Ac-5-ASA following a high-fat meal. Based on the 80%:125% rule for
`untransformed data, the plasma Cm ac values for 5-ASA and N-Ac-5-ASA were
`equivalent in the fed and fasted conditions. A slight increase (11%) was seen in
`5-ASA AUC0,. i „ 1 following a high-fat meal. These findings suggest that the delay in
`gastrointestinal (GI) transit induced by the high-fat meal allows more 5-ASA to be
`converted to its N-acetyl metabolite by the gastrointestinal mucosa; however, the
`overall systemic absorption of 5-ASA and its N-acetyl metabolite is not altered by a
`high-fat meal. In addition, there was no effect of a high-fat meal on cumulative fecal
`and urinary excretion of 5-ASA plus N-Ac-5-ASA. There was also no food effect on
`N-Ac-5-ASA urinary excretion. However, with a high fat meal there was a mean 30%
`decrease in fecal excretion of 5-ASA, a mean 16% increase in fecal excretion of
`N-Ac-5-ASA, and a mean 27% increase in 5-ASA urinary excretion.
`
`® (cid:9)
`
`® (cid:9)
`
`® (cid:9) No deaths or other serious adverse events were reported and no subject
`discontinued from therapy because of an AE.
`Comparable numbers of subjects reported AEs with mesalamine while fasting
`(n = 6) and with a high-fat meal (n = 5).
`® (cid:9) All AEs were mild or moderate in severity and resolved without sequelae.
`® (cid:9) Headache was the most commonly reported AE, occurring in 5 subjects overall
`(2 fasted, 2 fed, and 1 fasted/fed). Abdominal pain was the only other AE
`reported in more than one subject (1 fasted, 1 fed).
`Two subjects had changes in laboratory values that the Investigator considered to
`be clinically significant. One subject had unexplained elevations in AST with MP
`in the fed state that were > 3 times the upper limit of normal (ULN) on Study
`Day 1 (198 IU/L) and Study Day 4 (129 IU/L), which normalized by Day 11
`postdose (27 IU/L). One female subject had a urinalysis positive for red blood
`cells (> 50 hpf) with MP in the fed state on Study Day 4 that was probably
`associated with the subject's menses.
`Mesalamine pellets administered orally at 1600 mg (2 x 800 mg) in a single dose are
`safe and well tolerated in healthy subjects following an overnight fast or a high-fat
`meal. There is no effect of a standardized high-fat meal on the overall systemic
`absorption of 5-ASA and N-Ac-5-ASA or on the cumulative fecal and urinary
`excretion of 5-ASA plus N-Ac-5-ASA with MP administration. Therefore. NIP can be
`administered to subjects without regard to food.
`
`Date of Report:
`
`01 October 2007
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00373978
`
`Dr. Falk Ex. 2029
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1002 Clinical Study Report
`Final: 01 October 2007
`
`1 , (cid:9) TITLE PAGE ............................................................................................. ..............................1
`2. (cid:9) SYNOPSIS ................................................................................................................................ 2
`3, TABLE OF CONTENTS ........................................................................................................7
`4. LIST OF ABBREVIATIONS ...............................................................................................12
`5. ETHICS ..................................................................................................... .............................15
`5.1. (cid:9)
`Institutional Review Board/Independent Ethics Committee ...... .............................15
`5.2. (cid:9)
`Ethical Conduct of the Study ......................................................... .............................15
`5.3. (cid:9)
`Subject Information and Consent ................................................. .............................15
`6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .........................16
`7. INTRODUCTION ..................................................................................................................17
`8. STUDY OBJECTIVES ............................................................................. .............................19
`8.1. (cid:9)
`Primary Objective ........................................................................... .............................19
`8.2. (cid:9)
`Secondary Objectives ...................................................................... .............................19
`9. INVESTIGATIONAL PLAN .................................................................. .............................20
`9.1. (cid:9)
`Study Design .................................................................................... .............................20
`9.2. (cid:9)
`Discussion of Study Design ............................................................. .............................20
`9.3. (cid:9)
`Selection of Study Population ........................................................ .............................20
`Inclusion (cid:9) Criteria (cid:9) ...................................................................................................20
`9.3.1. (cid:9)
`9.3.2. (cid:9)
`Exclusion (cid:9) Criteria ..................................................................................................22
`9.3.3. (cid:9)
`Removal of Subjects from Therapy or Assessment ...............................................23
`9.4. (cid:9)
`Treatments ....................................................................................... .............................23
`9.4.1. (cid:9)
`Treatments (cid:9) Administered .......................................................................................23
`9.4.2. (cid:9)
`Identity of Investigational Product .........................................................................23
`9.4.3. (cid:9)
`Methods of Assigning Subjects to Treatment Groups ...........................................23
`9.4.4. (cid:9)
`Selection of Doses in the (cid:9) Study .............................................................................24
`9.4.5. (cid:9)
`Selection and Timing of Dose for Each Subject ....................................................24
`9.4.6. (cid:9)
`Blinding ..................................................................................................................24
`9.4.7. (cid:9)
`Prior and Concomitant Therapy .............................................................................24
`Treatment (cid:9) Compliance ...........................................................................................24
`9.4.8. (cid:9)
`9.5. (cid:9)
`Pharmacokinetic and Safety Variables ......................................... .............................24
`9.5.1. (cid:9)
`Pharmacokinetic and Safety Measurements Assessed and Schedule ....................24
`9.5.2. (cid:9)
`Pharmacokinetic Parameters ..................................................................................27
`9.5.2.1. (cid:9) Plasma Pharmacokinetic Parameters ................................................................ 27
`9.5.2.2. (cid:9) Urine Pharmacokinetic Parameters ................................................................... 27
`9.5.2.3. (cid:9) Fecal Pharmacokinetic Parameters ................................................................... 28
`
`7
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00373979
`
`Dr. Falk Ex. 2029
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
`
`CONFIDENTIAL (cid:9)
`
`MPPK1002 Clinical Study Report
`Final: 01 October 2007
`
`Processing of Biological (cid:9) Samples ..................................................................... 29
`9.5.2.4. (cid:9)
`Bioanalytical (cid:9) Methods .............................................................. .............................30
`9.5.3. (cid:9)
`Safety (cid:9) Assessments ................................................................. ............................... 3 0
`9.5.4. (cid:9)
`9.5.4.1. (cid:9) Adverse Events .................................................................. ............................... (cid:9) 30
`9.5.4.2. (cid:9) Physical Examination ......................................................... ............................... (cid:9) 31
`9.5.4.3. (cid:9) Vital (cid:9) Signs .......................................................................... ............................... (cid:9) 31
`9.5.4.4. (cid:9) Medical (cid:9) History (cid:9) ................................................................. ............................... (cid:9) 31
`9.5.4.5. (cid:9) Concomitant Medications .................................................. ............................... (cid:9) 31
`9.5.4.6. (cid:9) Clinical Laboratory Tests ................................................... ............................... (cid:9) 31
`Data Quality Assurance .................................................................. .............................32
`9.6. (cid:9)
`Statistical Methods and Determination of Sample Size ............................................33
`9.7. (cid:9)
`9.7.1. (cid:9)
`Statistical (cid:9) and Analytical Plans ................................................. .............................33
`9.7.1.1. (cid:9) General (cid:9) Considerations ...................................................... ............................... (cid:9) 3 3
`9.7.1.2. (cid:9) Analysis (cid:9) Sets ...................................................................... ............................... (cid:9) 3 3
`9.7.1.3. (cid:9) Disposition (cid:9) of Subjects ...................................................... ............................... (cid:9) 34
`9.7.1.4. (cid:9) Demographic and Baseline Data ........................................ ............................... (cid:9) 34
`9.7.1.5. (cid:9) Pharmacokinetic Analysis .................................................. ............................... (cid:9) 34
`Safety (cid:9) Analysis (cid:9) .................................................................. ............................... (cid:9) 35
`9.7.1,6. (cid:9)
`9.7.2. (cid:9)
`Sample Size Justification and Planned Power .......................... .............................35
`9.8. (cid:9)
`Changes in the Conduct of the Study or Planned Analyses .....................................36
`9.8.1. (cid:9)
`Changes in the Conduct of the Study ........................................ .............................36
`9.8.2. (cid:9)
`Changes in the Planned Analysis ...........................................................................36
`10. STUDY SUBJECTS .................................................................................. .............................38
`10.1. (cid:9) Disposition of Subjects .................................................................... .............................38
`10.2. (cid:9) Protocol Deviations ......................................................................... .............................38
`10.2.1. (cid:9)
`Enrollment Exceptions ...........................................................................................38
`10.2,2. (cid:9) Deviations During the Conduct of the Study .........................................................38
`10.2.3. (cid:9)
`Concomitant Medications ......................................................................................39
`11. PIfARMACOKINETIC AND STATISTICAL EVALUATION .......... .............................40
`11.1. (cid:9) Data Sets Analyzed ......................................................................... .............................40
`11.2. Demographic and Other Baseline Characteristics ....................... .............................40
`11.2.1. (cid:9)
`Subject Demographics ...........................................................................................40
`11.2.2. (cid:9)
`Subject Medical History ........................................................................................41
`11.2.3. (cid:9)
`Prior Medications ....................................................................................................41
`11.3. (cid:9) Measurements of Treatment Compliance .................................................................41
`11.4. (cid:9) Pharmacokinetic Results ................................................................ .............................41
`11.4.1. Phannacolcinetic Analysis ......................................................................................41
`11.4.1.1. Mixed Model Analysis of Variance for Pharmacokinetic Parameters .............. 41
`11.4.1.2. Plasma Pharmacokinetics .................................................................................. 42
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00373980
`
`Dr. Falk Ex. 2029
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Salix Pharmaceuticals, Inc. (cid:9)
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`MPPK1002 Clinical Study Report
`Final: 01 October 2007
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`11.4.1.3, (cid:9) Urinary Excretion .............................................................................................. 44
`11.4.1.4. (cid:9) Fecal Excretion ................................................................................................. 44
`11.4.2. (cid:9)
`Statistical and Analytical Issues .............................................................................45
`11.4.3. (cid:9)
`Tabulation of Individual Response Data ................................................................45
`11.4.4. (cid:9) Drug Dose, Drug Concentration, and Relationship to Response ...........................45
`11.4.5. (cid:9) Drug-Drug and Drug-Disease Interactions ............................................................45
`By-Subject Displays ...............................................................................................45
`11.4.6. (cid:9)
`11.4.7. (cid:9)
`Pharmacokinetic and Statistical Conclusions ........................................................45
`12. SAFETY EVALUATION ......................................................................................................47
`12.1. (cid:9) Extent of Exposure .......................................................................................................47
`12.2. (cid:9) Adverse Events .............................................................................................................47
`12.2.1. (cid:9) Overview of Adverse Events .................................................................................47
`12.2.2. (cid:9) Display (cid:9) of Adverse Events .....................................................................................48
`12.2.3. (cid:9) Analysis of Adverse Events ...................................................................................48
`12.2.4. (cid:9)
`Listing of Adverse Events by Subject ....................................................................49
`12.3. (cid:9) Deaths, Serious Adverse Events, and Other Significant Adverse Events ...............50
`12.4. (cid:9) Clinical Laboratory Evaluation ..................................................................................50
`12.4.1. (cid:9)
`Individual (cid:9) Laboratory Values ................................................................................50
`12.4.2. (cid:9)
`Evaluation of Each Laboratory Parameter .............................................................50
`12.4.2.1. (cid:9) Laboratory Values Over Time .......................................................................... 50
`12.4.2.2. (cid:9) Individual (cid:9) Subject Changes .............................................................................. 50
`12.4.2.3. (cid:9) Individual Clinically Significant Laboratory Abnormalities ............................ 50
`12.5. (cid:9) Vital Signs, Physical Findings, and Other Observations Related to Safety ...........51
`Safety Conclusions .......................................................................................................51
`12.6. (cid:9)
`13. DISCUSSION AND OVERALL CONCLUSIONS ............................................................53
`13.1. (cid:9) Discussion ......................................................................................... .............................53
`13.2. (cid:9) Conclusions ...................................................................................................................54
`14. TABLES AND FIGURES REFERRED TO BUT NOT INCLUDED IN THE TEXT ...5.5
`14.1. Demographic Data Summary Figures and Tables ....................................................55
`14.2. Pharmacokinetic Data Summary Figures and Tables ................. .............................60
`14.3. (cid:9) Safety Data Summary Figures and Tables ..............................................................317
`15. REFERENCES ......................................................................................... ............................361
`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
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`1\/1PPK1002 Clinical Study Report
`Final: 01 October 2007
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`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
`16.1.7. 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. Analytical Report No. 052-04001D
`16.1.9.3. Analytical Report No. 052-04002D
`16.1.9.4. Analytical Report No. 052-04003D
`16.1.9.5. Method Validation Report No. 052-04001 V
`16.1.9.6. Method Validation Report No. 052-03002V
`16.1.9.7. 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. Pharmacokinetic Evaluation Listings
`16.2.3. (cid:9)
`Safety Listings
`16.3. Case Report Forms
`16.4. Individual Subject Data Listings
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`NIPPK1002 Clinical Study Report
`Final: 01 October 2007
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`LIST OF IN-TEXT TABLES
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`Study Administrative Structure ...............................................................................16
`Table 1. (cid:9)
`Schedule of Assessments and Procedures ................................................................25
`Table2. (cid:9)
`Table 3. Assessments and Procedures for End of Study Period 2 or
`Early Discontinuation ................................................................................................26
`Table 4. (cid:9)
`Summary of Subject Disposition ..............................................................................38
`Table 5. (cid:9)
`Subject Demographics and Baseline Characteristics .............................................41
`Table 6. Plasma Pharmacokinetic Parameters for 5-ASA and N-Ac-5-ASA with
`Fasting and a High-Fat Meal (Mean ± SD, in fig) ...................................................43
`Table 7. Plasma Pharmacokinetic Parameters for 5-ASA and N-Ac-5-ASA with
`Fasting and a High-Fat Meal (Mean ± SD, in pmol) ..............................................43
`Table 8. Cumulative Urinary Excretion (0 to 96 Hours) of 5-ASA and N-Ac-5-ASA
`with Fasting and a High-Fat Meal (Mean ± SD) .....................................................44
`Table 9. Cumulative Fecal Excretion (0 to 96 Hours) of Soluble 5-ASA and N-Ac-5-
`ASA with Fasting and a High-Fat Meal (Mean ± SD) ............................................45
`Table 10. Overview of Adverse Events by Treatment .............................................................47
`Table11. Summary of All Adverse Events ...............................................................................48
`Table 12. Summary of Adverse Events Related to Mesalamine Pellets While Fasting
`andFollowing a High-fat Meal ................................................................................