Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: 11 October 2007
`
`1. TITLE PAGE
`
`Pr-§A.r«:jM_A 1i;:?_.?"£‘j§j{:,M..-55,
`as:
`,
`4"‘
`Me§,3‘v‘.§s2%1. §
`
`A ,.
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`
`CLINICAL STUDY REPOR
`
`A Multicenter, Randomized, Double—Blind, Plaeebo—Controlled Trial to
`Evaluate the Use ofMesalan1ine Pellet Formulation 1.5G QD to Maintain
`Remission from Mild to Moderate Ulcerative Colitis
`
`Name of Test/Investigational Drug:
`
`Indication Studied:
`
`Phase of Study:
`Protocol Number:
`
`Encapsulated Mesalamine Granules (eMG)
`(formerly referred to as Encapsulated
`Mesalamine Pellets [MP])
`Maintenance of remission of ulcerative colitis
`
`Phase 3
`MPUC3 003
`
`Study Initiation (First Subject, First Visit)
`Date:
`
`20 December 2004
`
`Study Completion (Last Subject, Last
`Visit) Date:
`Date of Study Report:
`
`26 April 2007
`11 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, Research and Development &
`Chief Development Officer
`Salix Pharmaceuticals, Inc.
`1700 Perimeter Park Drive
`
`Morrisville, NC 27560
`
`This study was conducted in accordance with the International Conference on Harmonisation
`Guidelines for Good Clinical Practice,
`the ethical principles that have their origin in the
`Declaration of Helsinki, and Title 21 of the United States Code of Federal Regulations
`Sections 50, 56, and 312.
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043192
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`l
`
`l
`
`‘
`
`‘
`
`‘
`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Final: ll October 2007
`
`2. SYNOPSIS
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`Name of Active Ingredient: Mesalamine
`Title of Study:
`A Miilticenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the
`Use of Mesalamine Pellet Formulation l.5G QD to Maintain Remission from Mild
`to Moderate Ulcerative Colitis
`
`1nVeSfigatm.(S) and
`Study Center(s):
`Publication (reference):
`
`Phase of Development:
`Stud‘, Periud
`(months/years):
`Obj can-Veg:
`
`Methodology:
`
`48 centers participated in this study (42 in the United States and 6 in Russia).
`
`No publications based on the study were available at the time of this clinical study
`report.
`
`Phase 3
`Date of first subject, first visit: 20 December 2004
`Date of last subject, last visit: 26 April 2007
`Primary objective: To compare the maintenance ofremission from mild to
`moderate ulcerative colitis (UC) as measured by rectal bleeding and endoscopic
`mucosal appearance after 6 months of treatment with encapsulated mesalamine
`granules (eMG) at 1.5 g QD, as compared with placebo.
`
`Secondary objective: To compare the safety and tolerability of long—term dosing
`with eMG at l.5 g QD as compared with placebo in the maintenance of remission
`from mild to moderate UC.
`
`This was a phase 3, multicenter, double—blind, randomized, plaeebo—eontI0lled study
`evaluating the effectiveness and safety of eMG l.5 g given once daily (QD)
`compared with placebo in approximately 300 subjects with demonstrated remission
`from UC. Eligible subjects were randomized in a 2:1 ratio (iactivezplacebo) to receive
`1 of 2 treatments: 1.5g eMG QD (four capsules total) or matching placebo capsules
`QD for 6 months.
`
`The study consisted of a Screening phase (completed within 7 days prior to
`randomization), a Treatment phase (6 months), and a Follow—up visit (2 weeks after
`end—of—study [EOS] visit). The Treatment phase consisted of 4 scheduled study
`visits: Visit l (Baseline)/Randomization (Day l), Visit 2 (Month l), Visit 3
`(Month 3), Visit 4/EOS (Month 6).
`
`A complete UC assessment using the revised Sutherland Disease Activity Index
`(DAI), including a sigmoidoscopy, was performed at or around the time of Screening
`and at .\/Ionth 6/EOS. An abbreviated UC assessment, without sigmoidoscopy, was
`performed at Baseline/Day l, .\/Ionth 1, Month 3. For subjects who discontinued
`prior to Month 6, a sigmoidoseopy, UC assessments, and safety assessments were
`performed at the Early Termination visit, if possible. A total Sutherland DAI score
`was calculated at Baseline by carrying forward the mucosal appearance
`(sigmoidoscopy) score from Screening,
`
`Safety assessments included monitoring of A135, clinical laboratory tests, collection
`of vital signs, monitoring of concomitant medications, and physical examinations (as
`needed).
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043193
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: 11 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`Name of Active Ingredient: Mcsalaminc
`Planned: 300 subjects; Screened: 356 subjects; Randomized: 305 subjects;
`Intent to Treat: 305 subjects; Per Protocol: 293 subjects;
`Safety population: 300 subjects
`
`Number of subjects:
`
`Key inclusion and
`exclusion criteria;
`
`Subjects were eligible if they met all of the following criteria:
`I Males or non-pregnant and non—lactating females 2 18 years-of-age.
`
`I Diagnosed with mild to moderate UC and had a history of at least one flare
`requiring therapeutic intervention Within the past 1 to 12 months.
`In remission for more than I month and less than 12 months from mild or
`
`moderate UC defined as the following revised Sutherland DAI component
`scores at screening:
`
`1. Rectal bleeding = 0 (Where 0 = none).
`
`2. Mucosal appearance = 0 or 1 (where 0 = intact mucosa with preserved
`or distorted vessels and l = erythema, decreased vascular pattern,
`granularity, no mucosal hemorrhage).
`
`Subjects were ineligible if any or more of the following applied:
`0
`A significant medical condition, including psychiatric, which in the opinion
`of the investor precluded study participation.
`
`Evidence of impaired immune function.
`
`Positive serology results for human immunodeficiency virus (HIV) or
`hepatitis (B or
`
`Received immunosuppressive therapy or corticosteroids within 30 days
`prior to screening.
`
`Clinically significant renal disease manifested by 1.5 times the upper limit
`of normal for serum creatinine or blood urea nitrogen (BUN) levels.
`Calculated creatinine clearance level of< 60 mL/min.
`
`Prior bowel surgery (except appendectomy).
`
`0
`
`0
`
`Test treatment, dust. and
`mode of administration,
`batch numb”:
`
`0.375 g of mesalamine granules (formerly referred to as mesalamine pellets) were
`encapsulated in a hard gelatin shell.
`1.5 g of eMCi (4 capsules) were administered orally QD, in the morning.
`eMG lot numbers: 0404177, 0404178, 0404179
`
`Reference treatment
`dose and mode of
`administratiom batch
`number:
`_____________________________________________________________
`Duration of treatment:
`
`I
`
`Matching placebo capsules (4 capsules) were administered orally QD, in the
`morning-
`Placebo lot number: 0404116
`
`Following a. screening period of up to 7 days, suhj ects participated in a. treatment
`period of6 months (24 weeks) and a folloW—up period of2 weeks. The total duration
`of study participation (including a 21-day visit window) was up to 29 weeks.
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043194
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: ll October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`
`I
`
`Name of Active Ingredient: Mesalamine
`
`Criteria for evaluation:
`
`13fficacyz
`
`The primary efficacy endpoint was the number and proportion of subjects who were
`relapse-flee after 6 months of treatment. Relapse or treatment failure was defined as
`a rectal bleeding score of l or more
`a mueosal appearance score of 2 or more, as
`described in the revised Sutherland Disease Activity Index (revised Sutherland DAI).
`In addition, subjects who experienced an UC flare or initiated medication used
`previously to treat UC were also considered a treatment failure. Early study
`termination was not considered a relapse unless the reason for early termination was
`lack of efficacy or discontinuation due to a UC-related AE. For subjects who
`terminated early for other reasons, the last revised Sutherland DAI assessment was
`used to determine relapse status.
`
`The secondary endpoints were as follows:
`1. The number and proportion of subjects in each level of change from
`baseline in rectal bleeding score at Months l, 3, and 6/EOS.
`
`The number and proportion otlsubjects in each level of change from
`baseline in mucosal appearance score at Month 6/EOS.
`
`The number and proportion of subjects in each level of change from
`baseline in physieian’s rating of disease activity at Months I, 3, and 6/EOS.
`
`The number and proportion of subjects maintaining the revised Sutherland
`DAI E 2 with no individual component of the revised Sutherland DAI > I
`and rectal bleeding = 0 at Month 6/EOS.
`
`Mean change from baseline in the revised Sutherland DAI at Month 6/EOS.
`
`Relapse-free duration, defined as the number of days between the start of
`study drug and the date that relapse was first detected or early termination
`from the study, plus 1 day.
`
`The number and proportion of subjects in each level of change from
`baseline in stool frequency score at Months 1, 3, and 6/EOS.
`
`Unless otherwise specified above, the Iast—observation—carried—torward (LOCF)
`methodology was used for imputing missing values of secondary efficacy endpoints
`for subjects wl1o terminated early.
`
`The safety endpoints were as follows:
`0
`Incidence of treatment—cmcrgent AES grouped by body system and
`evaluated by treatment group.
`
`Changes from baseline in clinical laboratory parameters at Months 1, 3, and
`6 by treatment group.
`
`Changes from baseline in vital sign measurements at Months 1, 3, and 6 by
`treatment group.
`
`Statistical mgthodsz
`
`In general, statistical testing used 2—sided tests at an 0. = 0.05 level of significance.
`All analyses were carried out using SAS, Version 8.2 or higher.
`
`All continuous Variables were summarized using descriptive statistics including
`number, mean, standard deviation, median, maximum, and minimum. All categorical
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043195
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: ll October 2007
`
`Name of Sponsor Company: Salix Pharrnaeeuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`Name of Active Ingredient: Mcsalamine
`Variables were summarized using frequency counts and percentages.
`
`Statistical methods
`
`(continued):
`
`The Intent—to—Treat (ITT) population included all randomized subjects who received
`at least I dose of study drug. The summary of demographics, summary of baseline
`characteristics, and analysis of efficacy parameters were performed for the ITT
`population.
`
`Tl1e Per Protocol (PP) population included all subjects in the ITT population without
`a major protocol deviation. Major protocol deviations included deviations from
`specific inclusion criteria; use of prohibited medications that would, in the opinion of
`the investigator, interfere with the study results; and wrongful allocation of study
`drug. The primary efficacy analysis was repeated for the PP population as a
`sensitivity analysis.
`
`The Safety population included all randomized subjects who received at least l dose
`of study drug and provided at least 1 post-baseline safety assessment.
`
`Primagy effieaey: A Coehran—Mantel-Haenszcl (CMH) test, controlling for country,
`was performed to determine statistical significance between treatment groups in the
`proportions of rclapsc—fi‘ee subjects at the end of 6 months of treatment.
`
`Secondag effi cacy: /\II secondary efficacy analyses were performed using the ITT
`population. Statistical testing among the secondary endpoints was performed in a
`hierarchical fashion in the order in which the secondary endpoints are listed.
`Significance tests were reported until a non—significant p-value was identified
`(p > 0.05). Once a non—significant p—VaIue occurred, all subsequent significance tests
`were considered exploratory in nature.
`
`All safety analyses were performed for the Safety population. Each analysis
`consisted ofa summary of data from each treatment group.
`
`Results:
`
`Disposition,
`Dcmugmphicgg and
`Basghnc
`Characteristics:
`
`Subject Disposition .
`Subjects randomized: 305
`Subject completing the study: 193 (63.3%)
`Subjects Withdrawn early: ll2 (36.7%)
`Adverse Eve11t: 54 (l7.7%)
`Lack of efficacy: 36 (1 L8‘?/o)
`Other: 22 (7.2%)
`
`Age
`
`Sex
`
`Median Age (Min, Max): 46 (I8, 82)
`< 65 years: 269 (88.2%)
`E 65: 36 (ll.8%)
`
`Male: 145 (47.5%)
`Female: 160 (52.5%)
`Baseline Disease Characteristics (weeks): Median (Min, Max)
`Disease duration: 199 (6.0, 1785.0)
`Time since most recent flare: 24.0 (4.0, 60.0)
`Duration ofcurrent remission: 13.0 (0.0, 57.0)
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043196
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: ll October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals; Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`Name of Active Ingredient: Mcsalaminc
`
`Efficacy Rgsuhsz
`
`The primary efficacy endpoint was the proportion of ITT subjects Who remained
`relapse—fi'ee after 6 months of treatment. The eMG treatment group had a larger
`proportion of 1'elapse—free subjects (78.9%) when compared with subjects treated
`with placebo (58.3%) at Month 6/EOS. This difference between the two treatments
`was statistically significant (p < 0.001) using a CMH test, demonstrating that eMG
`QD was more effective than placebo i11 maintaining remission of UC i11 subjects
`participating i11 this study. A supplementary post hoc analysis of the primary
`endpoint on the ITT population, using a chi-square test, produced a similar result
`(p < 0.001).
`
`Primary Efficacy Endpoint
`
`[N=305;P<0.0U1)
`
`(N=293, P=0.001)
`
`I eMG
`
`Successes
`
`Successes
`Farlures
`Month SIEOS Treatment Outcome
`
`The primary efficacy analysis was repeated as a sensitivity test using the PP
`population. Again, the eMG treatment group had a larger proportion of relapse—free
`subjects when compared with subjects treated with placebo (78.5% vs. 59.1%,
`p = 0.001).
`
`The effectiveness of eMG QD was further supported by the results of the secondary
`endpoints.
`
`The number and proportion of subjects at each level of change from baseline
`in the revised Sutherland DAI rectal bleeding component score at
`Month 6/EOS revealed a statistically significant difference (p = 0.008) in
`favor of the eMG group.
`
`A greater proportion ofplacebo subjects had an increased rnucosal
`appearance score at Month 6/EOS, although this difference in the change
`from baseline was not statistically significant (p
`0.098) using a CMH test
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043197
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: ll October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals; Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`
`l
`
`Name of Active Ingredient: Mcsalaminc
`controlling for country. However, a statistically significant difference
`between the treatment groups (p= 0.035) was noted using a chi—square test.
`
`Efficacy Results
`(continued):
`
`The number and proportion of subjects at each level of change from baseline
`in the revised Sutherland DAI physician‘s rating of disease activity
`component score at Month 6/EOS revealed a statistically significant
`difference (p = 0.005) in favor of the eMG group.
`
`A larger proportion (70.3% vs. 53.1%; p 3 0.003) of subjects receiving er\/IG
`versus placebo were classified as treatment successes (maintaining the revised
`Sutherland DAI score of S 2 with no individual component of the revised
`Sutherland DAI > l and rectal bleeding = 0).
`
`A smaller mean change (0.9 vs. 2.0; p = 0.001) from baseline was observed in
`the eMG group compared with placebo group in the revised Sutherland DAI
`total score.
`
`/\ higher probability of remaining relapse—free was observed in the eMG
`group, (77%; 95% CI: 0.7l , 0.83) compared with the placebo group (56%;
`95% Cl: 0.46, 0.67) over the 6 month course of the study.
`
`The number and proportion of subjects at each level of change from baseline
`in the revised Sutherland DAI stool frequency component score at
`Month 6/EOS revealed a statistically significant difference (p = 0.005) in
`favor of the eMG group.
`
`Saf"5lY R"35”ll53
`
`Encapsulated mesalamine granules administered l .5 g QD over 6 months for the
`maintenance of remission of ulcerative colitis were safe and well tolerated in this
`
`study. Exposure to eMG was longer (mean = 142.8 days) than placebo (mean = l l8_2
`days).
`
`The safety results are summarized here:
`
`0
`
`The percentage of subjects experiencing any TEAE was essentially
`identical between the eMG and placebo groups (64.1% eMG, 63.8%
`placebo) and most TE/—\Es were mild or moderate in intensity.
`
`Ulcerative colitis flare was more than twice as common in the placebo
`group (26.6%) compared with the eMG group (11.2%). Headache; a
`known side effect of mesalarnine, was slightly more common in the eMG
`group ( I l .2%) than in the placebo group (7.4%).
`
`There were no deaths during the study and only 4 SAEs (2 in each study
`group); l subject in the placebo group experienced an SAE of UC
`considered to be possibly related to study drug.
`
`A smaller percentage of subjects in the eMG group prematurely
`discontinued the study due to a TEAE (l5.0"/5) compared with subjects in
`the placebo group (27.7%).
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043198
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Final: 11 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals; Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (formerly referred to as Mesalamine
`Pellets [MP])
`Name of Active Ingredient: Mesalamine
`
`0
`
`Events related to kidney and liver function, which are a potential concern
`with mesalamine administration. were rare and did not differ in
`frequency between the treatment groups.
`
`In summary, eMG were well tolerated over 6 months with a dosing regimen of
`1.5 g QD and the safety profile did not differ in any clinically meaningful way from
`that of paeebo. The table below presents an overall summary of safety.
`
`Overall Summary of Safety
`
`Catepog
`Subjects reporting any TEAE
`Subjects reporting TEAES by intensity”
`Mild
`Moderate
`Severe
`
`Subjects reporting TEAES possibly related
`to study drug
`Subject Deaths
`Subjects reporting any SAE
`Subjects reporting any TEAE leading to
`study discontinuation
`Siibjects with any SAE leading to study
`discontinuation
`
`elVlG
`N=206
`
`Safety Population
`Placebo
`N=94
`
`Total
`N=300
`
`11 (%)
`132 (64.1)
`
`11 C70)
`60 (63.8)
`
`n (%)
`192 (64.0)
`
`53 (25.7)
`62 (30.1)
`17 (8.3)
`
`17 (18.1)
`39 (41.5)
`4 (4.3)
`
`70 (23.3)
`101 (33.7)
`21 (7.0)
`
`28 (13-6)
`
`15 (16-0)
`
`43 (14-3)
`
`0
`2 (1.0)
`31
`(15.0)
`0 (0-0)
`
`0
`2 (2.1)
`26 2 .
`( 7 7)
`1 (1.0)
`
`5
`
`0
`4 (1.3)
`19.0
`
`7 (
`1 (0-3)
`
`)
`
`Abbreviations: AF, : adverse event; eMG : encapsulated mesalamine granules; N : number;
`QD — once daily; SAE — serious adverse event; TEAE — treatment emergent adverse event
`a
`Percentage reflects the number of subjects as a. proportion of the total number of subj eets
`enrolled in the treatment group.
`b : If a. subject experienced more than one TEAE, the subject is counted only once for the
`worst severity.
`
`Encapsulated mesalamine granules differ from other mesalamine formulations by
`combining both delayed release and extended release mechanisms designed to deliver
`more mesalamine to the site of therapeutic action while reducing systemic exposure.
`This study has shown eMG to be effective, safe, and well tolerated for the long term
`maintenance of remission of UC. If approved, eMG would be the only product
`available for this indication with once daily dosing, providing physicians and patients a
`more convenient alternative for maintaining remission from UC.
`
`Conclusions:
`
`I
`
`Date 0*’ ReP0rt=
`
`11 October 2007
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043199
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: ll October 2007
`
`. TABLE OF CONTENTS
`
`. TITLE PAGE ......................................................................................................................... ..I
`
`. SYNOPSIS .............................................................................................................................. ..2
`
`. TABLE OF CONTENTS ...................................................................................................... ..9
`
`. LIST OF ABBREVIATIONS ............................................................................................. ..17
`
`. ETHICS ................................................................................................................................ ..19
`
`5.].
`
`5.2.
`
`5.3.
`
`Institutional Review Board/Independent Ethics Committee ...................................l9
`
`Ethical Conduct of the Study .................................................................................... ..19
`
`Subject Information and Consent ..............................................................................19
`
`INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ....................... ..20
`
`INTRODUCTION................................................................................................................ ..21
`
`.
`
`.
`
`. STUDY OBJECTIVES ..........................................................................................................24
`
`8.1.
`
`8.2.
`
`Primary Objective ...................................................................................................... ..24
`
`SecondaryObjective .................................................................................................. ..24
`
`.
`
`INVESTIGATIONAL PLAN ............................................................................................. ..25
`
`9.1.
`
`9.2.
`
`Overall Study Design and Plan Description ............................................................ ..25
`
`Discussion of Study Design, Including the Choice of Control Groups.................. ..28
`
`Selection of Study Population .....................................................................................29
`9.3.
`9.3.1.
`Inclusion Criteria ................................................................................................. ..29
`
`9.3.2.
`
`Exclusion Criteria ................................................................................................ ..30
`
`9.3.3.
`
`Removal of Subjects from Therapy or Assessment ............................................. ..3l
`
`9.4.
`
`Treatments .................................................................................................................. ..32
`
`9.4.1.
`
`Treatments Administered ..................................................................................... . .32
`
`9.4.2.
`
`Identity of Investigational Product ....................................................................... ..32
`
`9.4.3.
`
`9.4.4.
`
`Method of Assigning Subjects to Treatment Groups ........................................... ..34
`
`Selection of Doses in the Study ........................................................................... ..34
`
`9.4.5.
`
`Selection and Timing of Dose for Each Subject .................................................. ..34
`
`9.4.6.
`
`9.4.7.
`
`Blinding ................................................................................................................ ..34
`
`Prior and Concomitant Therapy ........................................................................... ..35
`
`9.4.8.
`
`Treatment Compliance ......................................................................................... ..37
`
`9.5.
`
`Efficacy and Safety Variables ................................................................................... ..38
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00043200
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`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 9
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`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: 11 October 2007
`
`9.5.1.
`
`Efficacy and Safety Measurements Assessed and Schedule of Events ............... ..38
`
`9.5.2.
`
`Appropriateness of Measurements ....................................................................... ..53
`
`9.5.3.
`
`Primary Efficacy Variable ................................................................................... ..53
`
`9.6.
`
`9.7.
`
`Data Quality Assurance............................................................................................. ..53
`
`Statistical Methods Planned in the Protocol and Determination of Sample Size ..54
`
`9.7.1 .
`
`Statistical and Analytical Plans ............................................................................ ..54
`
`9.7.2.
`
`Statistical Power and Determination of Sample Size .......................................... ..60
`
`9.8.
`
`Changes in the Conduct of the Study or Planned Analyses ................................... ..60
`
`9.8.1.
`
`9.8.2.
`
`Changes in the Conduct of the Study ................................................................... ..61
`
`Changes in the Planned Analyses ........................................................................ ..62
`
`10. STUDY SUBJECTS ...............................................................................................................63
`
`10.1. Disposition ofSubjects ............................................................................................... ..63
`10.2. Protocol Deviations .................................................................................................... ..65
`
`11. EFFICACY EVALUATION ............................................................................................... ..67
`
`11.1. Data Sets Analyzed .................................................................................................... ..67
`
`11.2. Demographics and Other Baseline Characteristics ................................................ ..68
`
`11.2.1.
`1 1.2.2.
`
`Subject Demographics ......................................................................................... ..68
`Baseline Characteristics ....................................................................................... ..69
`
`11.3. Measurements of Treatment Compliance ............................................................... ..72
`
`11.4. Efficacy Results and Tabulations of Individua.l Subject Data .................................73
`
`11.4.1. Analysis ofEfficaey ............................................................................................. ..73
`
`11.4.2.
`
`Statistical and Analytical Issues ........................................................................... ..91
`
`1 1.4.3.
`
`Tabulation of Individual Response Data.............................................................. ..92
`
`11.4.4. Drug Dose, Drug Concentration, and Relationship to Response ......................... ..93
`
`11.4.5. Drug-drug and Diug-disease Interactions ............................................................ ..93
`
`I 1.4.6.
`
`By—Subject Displays ............................................................................................. ..93
`
`11.4.7.
`
`Efficacy Conclusions ........................................................................................... ..93
`
`I2. SAFETY EVALUATION .................................................................................................... ..95
`
`12.1. Extent of Exposure ..................................................................................................... ..95
`12.2. Adverse Events ........................................................................................................... ..96
`
`12.2.1. Brief Summary of Adverse Events ...................................................................... ..96
`
`12.2.2. Display of Adverse Events ................................................................................... ..97
`
`12.2.3. Analysis of Adverse Events ................................................................................. ..98
`
`CONFIDENTIAL INFORMATION
`
`SAL|X0O04320’I
`
`Dr. Falk Ex. 2049
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 10
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesalamine Granules
`
`MPUC3003 Clinical Study Report
`
`Fi11al: 11 October 2007
`
`12.2.4.
`
`Listing ofAdverse Events by Subject ................................................................ .. 1 04
`
`12.3. Deaths, Other Serious Adverse Events, and Other Significant
`Adverse Events ........................................................................................................ ..104
`
`12.3.1.
`
`Listing of Deaths, Other Serious Adverse Events, and Other
`
`Significant Adverse Events ................................................................................ ..104
`
`12.3.2. Narratives of Deaths, Other Serious Adverse Events, and Certain Other
`
`Significant Adverse Events ................................................................................ .. I 06
`
`12.4. Clinical Laboratory Evaluation .............................................................................. ..106
`
`12.4.1.
`
`Listing of Individual Laboratory Measurements by Subject and Each
`
`Abnormal Laboratory Value .............................................................................. ..106
`
`12.4.2.
`
`Evaluation of Each Laboratory Parameter ......................................................... .. 107
`
`12.5. Vital Signs, Physical Findings, and Other Observations Related to Safety ....... ..l13
`
`12.5.1. Vital Signs .......................................................................................................... ..113
`
`12.5.2.
`
`Prior, Concomitant, and Post—Treatment Medications ....................................... ..I 13
`
`12.6. Safety Conclusions ................................................................................................... ..ll5
`
`13. DISCUSSION AND OVERALL CONCLUSIONS ........................................................ ..117
`
`13.1. Discussion.................................................................................................................. ..l17
`
`13.2. Conclusions ............................................................................................................... ..l18
`
`14. TABLES AND FIGURES REFERRED T() BUT NOT INCLUDED
`
`I.\l THE TEXT .................................................................................................................... ..l19
`
`14.1. Disposition, Demographic, and Baseline Characteristics Data
`
`Summary Tables and Figures ................................................................................ ..123
`
`14.1.1.
`
`Summary of Subject Disposition by Treatment Group ...................................... .. 124
`
`14.1.2.
`
`Summary ofNumber of Subjects Randomized at Each Site by
`
`Treatment Group ................................................................................................ .. 125
`
`14.1.3.
`
`Summary of Number of Subjects in Each Study Population by
`
`Treatment Group ................................................................................................ .. 133
`
`14.1.4.
`
`Summary of Demographics by Treatment Group .............................................. .. 134
`
`14.1.5.
`
`Summary of Demographics by Country and Treatment Group ......................... .. 136
`
`14.1.6.
`
`Summary of Medical History and Baseline Disease Characteristics
`
`by Treatment Group ........................................................................................... ..140
`
`14.1.7.
`
`Summary oi°MedicaI History and Baseline Disease Characteristics
`
`by Country and Treatment Group ...................................................................... ..143
`
`14.1.8.
`
`Summary of Baseline Revised Sutherland DAI Component Scores
`
`by Treatment Group ........