Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`1. TITLE PAGE
`
`:5'as3’=,é:ws=2::;+:-c
`
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`
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`
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`
`CLINICAL STUDY REPORT
`
`A Multicenter, Randomized, Double-Blind, Placebo—ControIled Trial to
`
`Evaluate the Use of Mesalamine 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
`MPUC3004
`
`Study Initiation (First subject, first visit)
`Date:
`
`24 December 2004
`
`Study Completion (Last subject, last visit)
`Date:
`Date of Study Report:
`
`08 August 2007
`26 October 2007
`
`Study Sponsor:
`
`Name of Sponsor Signatory:
`
`Salix Pharmaceuticals, Inc
`1700 Perimeter Park Drive
`
`Morrisville, North Carolina, USA 27 560
`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|X00048657
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`2. SYNOPSIS
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated l\/Iesalamine Granules (eMG) (fonnerly referred to as Mesalamine Pellets
`IMPI)
`
`Name of Active Ingredient: Mesalamine
`Title of Study:
`A Multicenter, 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
`
`[,weSfigamr(s) and
`Study Center(s):
`Pumicafion (reference):
`
`Forty study centers participated in this study (32 in the United States and 8 in Russia).
`
`No publications based on the study were available at the time of this clinical study
`report.
`
`Phase of Development:
`
`Phase 3
`
`Study Period
`(rnonths/years):
`Objectives:
`
`Date of first subject, first visit: 24 December 2004
`Date of last subject, last visit: 08 August 2007
`Primary objective: To compare the maintenance of remission from mild to moderate
`uleerative 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 given once daily (QD), as compared with placebo.
`
`Secondary objective: To compare the safety and tolerability of long-term dosing
`with eMG at l.5 g QD (eMG QD) as compared with placebo in the maintenance of
`remission from mild to moderate UC.
`
`Methodology:
`‘
`
`Approximately 250 eligible subjects were randomi/,ed in a 2:1 ratio to receive 1 o[‘2
`treatments: eMG 1.5 g QD 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 1 (Baseline)/Randonrization (Day I), Visit 2 (Month 1), 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 Month 6/EOS. An abbreviated UC assessment, without sigmoidoscopy, was
`performed at Baseline/Day 1, Month 1, and Month 3. For subjects who discontinued
`prior to Month 6, a sigmoidoscopy. UC assessments, and safety assessments were
`performed at the Early Termination visit, if possible. A total revised Sutherland DAI
`score was calculated at Baseline by carrying forward the rnucosal appearance
`(sigmoidoscopy) score from Screening.
`
`Safety assessments included monitoring of adverse events (AE3), clinical laboratory
`tests. collection of vital signs, monitoring of concomitant medications, and symptom—
`directed physical examinations (as needed).
`
`;
`
`1
`
`I
`
`t
`
`I
`
`;
`
`Nllmbel‘ Of Subjects!
`
`Planned: 250 subjects; Screened: 324 subjects; Randomized: 257 subjects;
`Intent to Treat: 257 subjects; Per Protocol: 247 subjects;
`Safety Population: 252 subjects
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048658
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (fonnerly referred to as Mesalamine Pellets
`IMPI)
`
`Name of Active Ingredient: Mesalarnine
`
`Kev inclusion and
`cxculusion criteria,
`
`Subjects were eligible if they met all of the following criteria:
`0 Males or non-pregnant and non—lactating females 2 l8 years—of—age.
`
`0
`
`Diagnosed with mild to moderate UC and had a history of at least one flare
`requiring therapeutic intervention within the past I to 12 months.
`In remission for more than 1 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 O = intact mucosa with preserved
`or distorted vessels and 1 = erythema, decreased vascular pattern,
`granularity, no mucosal hemorrhage).
`
`Subjects were ineligible if one or more of the following applied:
`-
`A significant medical condition, including psychiatric. which in the opinion
`of the investigator precluded study participation.
`
`Evidence of impaired immune function.
`
`Positive serology results for human immunodeficiency virus (HIV) or
`hepatitis (B or C).
`
`Received immunosuppressive therapy or corticosteroids within 30 days prior
`to screening.
`Clinically significant renal disease manifested by l.5 times the upper limit of
`normal for serum creatinine or blood urea nitrogen (BUN) levels.
`
`Calculated creatinine clearance level of S 60 mL/min.
`
`Prior bowel surgery (except appendectomy).
`
`-
`
`0
`
`Test treatment, dose and
`mode of administration,
`
`0.375 g of mesalamine granules (formerly referred to as mesalamine pellets) were
`‘
`’
`encapsulated in a hard gelatin shell.
`
`Imtch ““mI"“"
`
`1.5 g of eMG (4 capsules) were administered orally QD, in the morning,
`
`eMG lot numbers: 0404178, 0404179, 0601686.
`
`Refemnce “"e"‘tm_"m*
`dose and mode of
`
`administration, batch
`number:
`
`Duration of treatment:
`
`Matching placebo capsules (4 capsules) were administered orally QD in the morning.
`
`Placebo lot numbers: 0404116. 04041 17.
`
`Following a screening period of up to 7 days. subjects participated in a treatment
`period of 6 months (24 weeks) and a follow-up period of 2 weeks. The total dtnation
`of study participation (including a 21-day visit. window) was up to 29 weeks.
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048659
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (fonnerly refened to as Mesalamine Pellets
`IMPI)
`
`Name of Active Ingredient: Mesalarnine
`Criteria for evaluation:
`
`Efficacy:
`'
`
`The primary efficacy endpoint was the number and proportion of subjects who were
`relapse-free after 6 months of treatment. Relapse or treatment failure was defined as
`a rectal bleeding score of l or more argl a mucosal appearance score of 2 or more, as
`described in the revised Sutherland Disease Activity Index (DAI). In addition,
`subjects who experienced a 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
`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:
`
`l. The number and proportion of subjects in each level of change from baseline
`in rectal bleeding score at Months 1. 3, and 6/EOS.
`
`The number and proportion of subjects 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 physiciarfs rating of disease activity at Months I, 3. and 6/EOS.
`
`The number and proportion of subjects maintaining the revised Sutherland
`DAI 5 2 with no individual component of the revised Sutherland DAI > 1
`and rectal bleeding = O 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 last-observation-carried-forward (LOCF)
`methodology was used for imputing missing values of secondary efficacy endpoints
`for subjects who terminated early.
`
`Safety endpoints and assessments were as follows:
`
`0
`
`Incidence of treatment-emergent AEs (TEAE) grouped by body system and
`evaluated by treatment group.
`
`Changes from baseline in clinical laboratory parameters at Months I, 3, and
`6 (or EOS) by treatment group.
`
`Changes from baseline in vital sign measurements at Months I, 3, and 6, and
`follow-up by treatment group.
`
`Concomitant medications by therapeutic class and preferred term by each
`treatment group.
`
`‘
`
`‘
`
`‘
`
`I
`
`I
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048660
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalaniine Granules (eMG) (fonnerly refened to as Mesalamine Pellets
`IMPI)
`
`Name of Active Ingredient: Mesalarnine
`Smfisfical methods:
`In general, statistical testing used 2—sided tests at an CL = 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
`variables were summarized using frequency counts and percentages.
`
`The 1ntent—to-Treat (ITT) population included all randomized subjects who received
`at least 1 dose of study drug. The summary of demographics, summary ofbaseline
`characteristics, and analysis of efficacy parameters were performed for the ITT
`population.
`
`The Per Protocol (PP) population included all subjects in the lTT population without
`a major protocol deviation. Maj or 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 consisted of all randomized subjects who received at least
`1 dose of study drug and provided at least 1 post—baselii1e safety assessment.
`
`efficacy: A Cochran-Mantel—Haenszel (CMH) test, controlling for country,
`was performed to determine statistical significance between treatment groups in the
`proportions of relapse-free subjects at the end of 6 months of treatment.
`
`Secondag efficacy: All 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-sigriificant p-value occurred, all subsequent significance tests
`were considered exploratory in nature.
`
`All safety analyses were performed for the Safety population. Each analysis consisted
`of a summary of data from each treatment group.
`
`Results:
`
`Disposition;
`Demographics) and
`Baseline
`Characteristics:
`
`.
`Subject Disposition:
`Subjects randonnzed: 257
`Subject conipleting the study: 176 (68.5%)
`Subjects withdrawn early: 81 (31.5%)
`Adverse Event‘: 15 (58%)
`Lack of efficacy: 47 (18.3%)
`Other: 19 (7.4%)
`Age: Median Age (Min, Max): 46 (18, 82)
`< 65 years: 23] (89.9%)
`2 65: 26 (10.1%)
`Sex: Male: 122 (47.5%)
`Female: 135 (52.5%)
`Baseline Disease Characteristics (Median [Min, Max] weeks):
`Disease duration: 156 (9, 2151)
`Time since most recent flare: 20 (5, 93)
`Duration of current remission: 13 (2, 59)
`
`CONFIDENTIAL INFORMATION
`
`SAL|X0O04866’I
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated lvlesalamine Granules (eMG) (fonnerly referred to as Mesalamine Pellets
`lMPl)
`
`Name of Active Ingredient: Mesalarnine
`
`Efficacy Results:
`
`The primary efficacy endpoint was the proportion of ITT subjects who remained
`relapse—free after 6 months of treatment. The eMG treatment group had a larger
`proportion of relapse-free subjects (7 9.9%) when compared with subjects treated with
`placebo (66.7%) at Month 6/EOS. This difference between the two treatments was
`statistically significant (p = 0.029) using a CMH test, demonstrating that eMG was
`more effective than placebo in maintaining remission of UC in subjects participating
`in this study.
`
`;
`
`i
`
`Primary Efficacy Endpoint
`
`leMG
`
`EIP|acebu
`
`(N = 257: P = 0.229)
`
`_
`
`(N = 247;? = 0.034)
`
`<90
`
`on0
`
`~:o
`
`0'):2
`
`
`
`Subjects(2%) 33
`
`oz9
`
`M0
`
`0
`
`Success
`
`Success
`Failure
`Month 6 Treatment Outcome
`
`The primary efiicacy 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 (80. 1% vs. 67.4%,
`p : 0.034).
`
`The effectiveness of eMG was further supported by the results of 2 exploratory
`secondary endpoint analyses:
`
`0
`
`A larger proportion of eMG subjects met the 3 criteria of maintaining a
`revised Sutherland DAI S 2 with no individual component > 1 and rectal
`bleeding = 0 at Month 6/EOS, compared with subjects receiving placebo
`(72.05 vs. 58.1%, p = 0.039).
`
`The eMG group had a lower risk of relapse than the placebo group over the
`6 month course of the study (hazard ratio = 0.57, p = 0.024).
`
`The following additional secondary endpoints demonstrated differences between the
`eMG and placebo groups but did not reach statistical significance:
`
`0
`
`A larger proportion of eMG subjects had no increase in the rectal bleeding
`subscore of the revised Sutherland DAT from baseline to Month 6/EOS
`(84.7% vs. 75.3%).
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048662
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated Mesalamine Granules (eMG) (fonnerly referred to as Mesalamine Pellets
`IMPD
`
`Name of Active Ingredient: Mesalamine
`0
`A larger proportion of eMG subjects had no increase in the mucosal
`appearance subscore of the revised Sutherland DA1 from baseline to Month
`6/EOS (79.2% vs. 74.1%).
`
`A larger proportion of eMG subjects had no increase in the physician‘s
`rating of disease subscore of the revised Sutherland DA1 from baseline to
`Month 6/EOS (84.8% vs. 75.3%).
`
`The eMG group showed a smaller mean change in the revised Sutherland
`DA] total score from baseline to Month 6/EOS (0.7 vs. 1.2).
`
`A larger proportion of eMG subjects had no increase in the stool frequency
`subscore of the revised Sutherland DA1 from baseline to Month 6/EOS
`(82.9% vs. 76.3%).
`
`Safe“; Results:
`'
`
`Encapsulated mesalamine grzmules administered 1.5 g QD over 6 months for the
`maintenance of remission of ulcerative colitis were safe and well tolerated in this
`study. Mean exposure to eMG was longer (147.84 days) than placebo (133.90 days).
`
`The safety results are summarized below:
`
`0
`
`The percentage of subjects experiencing any TEAE was lower in the eMG
`group compared with the placebo group (eMG: 53.4% vs. placebo: 63.7%)
`and mo st TEAES were mild or moderate in intensity.
`Ulcerative colitis flare was twice as common in the placebo group (22.0%)
`compared with the eMG group (10.6%). Headache, a known side effect of
`mesalamine, was more common in the eMG group (10.6%) than iii the
`placebo group (7.7%),
`There were no deaths during the study.
`
`Five serious adverse events (SAEs) in 4 subjects (2 subjects ir1 each study
`group) were reported. None of the SAES were considered to be possibly
`related to study drug.
`
`The percentage of subjects that prematurely withdrew from the study due to
`a TEAE was similar between the treatment groups (eMG: 5.5%, placebo:
`6.6%).
`
`Few events related t.o hepatic, renal, and pancreatic function. which are a
`potential concern with mesalamine administration, were observed.
`In summary, eMG 1.5 g taken once per day for up to 6 months was safe and well
`tolerated; the safety profile did not differ in any clinically meaningful way from that
`of placebo.
`
`The table below also presents an overall summary of safety.
`
`I
`
`I
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048663
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`Name of Sponsor Company: Salix Pharmaceuticals, Inc.
`Name of Finished Product: Encapsulated lvlesalamine Gianules (eMG) (fonnerly referred to as Mesalamine Pellets
`IMPD
`
`Name of Active Ingredient: Mesalamine
`
`Overall Summary of Safety
`
`Safety Population
`Placebo
`
`eMG
`
`Total
`
`‘
`CM6g01‘>'
`Subjects reporting any TEAE
`Subjects reporting TEAES by intensity“
`Mild
`Moderate
`Severe
`Subjects reporting any TEAE possibly
`related to study drug
`Subject Deaths
`§I|:1I3'egc‘:[snr§p‘()lg't1ng any t1eatment—
`Subjects reporting any TEAE leading
`to study discontinuation
`Subjects reporting any SAE leading to
`study discontinuation
`
`N=161
`n (0/0)
`86 (53.4)
`
`40 (24.8)
`41 (25.5)
`5 (3.1)
`11 (6,8)
`
`0
`
`0
`
`N=91
`n (9/0)
`58 (63.7)
`
`36 (39.6)
`17 (18.7)
`5 (5.5)
`10 (11.0)
`
`0
`2 (2.2)
`6 (6.6)
`
`N=252
`n (%)
`144 (57.1)
`
`76 (30.2)
`58 (23.0)
`10 (4.0)
`21 (83)
`
`0
`4 (1.6)
`15 (6.0)
`
`0
`
`0
`
`Abbreviations: AE = adverse event; CMG = encapsulated mesalamine granules;
`SAE = serious adverse event; TEAE = treatment emergent adverse event
`a
`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.
`
`I
`y
`
`I
`
`Conclusions:
`
`Date of Report:
`
`26 October 2007
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048664
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`3. TABLE OF CONTENTS
`
`. TITLE PAGE ......................................................................................................................... ..1
`
`SYNOPSIS .............................................................................................................................. ..2
`
`. TABLE OF CONTENTS ........................................................................................................9
`
`. LIST OF ABBREVIATIONS ............................................................................................. ..20
`
`o
`
`.
`
`.
`
`.
`
`.
`
`E‘
`
`/L. oooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo so
`*5
`
`5.1.
`
`5.2.
`
`5.3.
`
`Institutional Review Board or Independent Ethics Committee ............................ ..22
`
`Ethical Conduct of the Study .................................................................................... ..22
`
`Subject Information and Consent ............................................................................ ..22
`
`INVESTIGATORS AND STUDY ADIVIINISTRATIVE STRUCTURE ....................... ..23
`
`INTRODUCTION................................................................................................................ ..24
`
`STUDY OBJECTIVES ........................................................................................................ ..27
`
`8.1.
`
`8.2.
`
`Primary Objective ...................................................................................................... ..27
`
`Secondary Objective .................................................................................................. ..2’7
`
`.
`
`INVESTIGATIONAL PLAN ............................................................................................. ..28
`
`9.1.
`
`9.2.
`
`9.3.
`
`Overall Study Design and Plan Description ............................................................ ..28
`
`Discussion of Study Design, Including the Choice of Control Groups .................. ..31
`
`Selection of Study Population ................................................................................... ..32
`Inclusion Criteiia .................................................................................................
`
`9.3.2.
`
`Exclusion Criteria ................................................................................................ .33
`
`9.3.3.
`
`Removal of Subjects from Therapy or Assessment .............................................. .35
`
`9.4.
`
`Treatments .................................................................................................................. ..36
`
`l.
`
`Treatments Administered ..................................................................................... .36
`
`9.4.2.
`
`Identity of.lnvestigationa.| Product ....................................................................... .36
`
`9.4.3.
`
`9.4.4.
`
`9.4.5.
`
`9.4.6.
`
`9.4.7.
`
`Method of Assigning Subjects to Treatment Groups ........................................... ..37
`
`Selection o'l’Doses in the Study ........................................................................... ..37
`
`Selection and Timing of Dose for Each Subject .................................................. .38
`
`Blinding ................................................................................................................ .38
`
`Prior and Concomitant Therapy ........................................................................... .39
`
`9.4.8.
`
`Treatment Compliance ......................................................................................... ..4O
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048665
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 9
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`1\/IPUC3 004 Clinical Study Report
`
`Final: 26 October 2007
`
`9.5.
`
`Efficacy and Safety Variables ................................................................................... ..41
`
`9.5.1.
`
`Efficacy and Safety Measurements Assessed and Schedule of Events ............... ._41
`
`9.5.1.1. Efficacy Assessments and Endpoints .............................................................. ..44
`
`9.5.1
`
`Safety Assessments and Endpoints .................................................................. . .46
`
`9.5.1.3.
`
`Screening Period Assessments and Procedures ............................................... ..51
`
`9.5.1.4. Visit ‘I. (Baseline)/Randornization (Day 1) Assessments and Procedures ........ .52
`
`9.5.1.5. Week 2 (Day 14) Telephone Contact ............................................................... .52
`
`9.5.1.6. Visit 2 Assessments and Procedures (Month 1 [Day 28 :: 7 days]) ................ .53
`
`9.5.1.7. Month 2 (Day 56) Telephone Contact .............................................................. .53
`
`9.5.1.8. Visit 3 Assessments and Procedures (Month 3 [Day 84 :: 14 days]) .............. .53
`
`9.5.1.9. Month 4 (Day 112) Telephone Contact ............................................................ .54
`
`9.5.1.10. Month 5 (Day I40) Telephone Contact ........................................................... ..54
`
`9.5.1.11. Visit 4/EOS (Month 6 [Day I68 :: 21 days])/Early Termination
`Assessments and Procedures ............................................................................ .54
`
`951.12. Follow-up Period Assessments and Procedures .............................................. .55
`9.5.1.13. Unscheduled Visits ........................................................................................... .55
`
`9.5.2.
`
`953.
`
`Appropriateness of Measurernents ....................................................................... .56
`
`Primary 1:-Efficacy Variable .................................................................................... .56
`
`9. 54.
`
`Drug Concentration Measurements ..................................................................... .56
`
`9.6.
`9.7.
`
`Data Quality Assurance ............................................................................................. ..56
`Statistical Methods Planned in the Protocol and Determination of
`
`Sample Size ................................................................................................................ ..57
`
`9.7.1.
`
`Statistical and Analytical Plans ............................................................................ ..57
`
`9.7.1. 1. Analysis Populations ......................................................................................... .57
`
`9.7.1.2. Demographic and Baseline Variables ............................................................... .58
`
`9.7.1
`
`Subject Disposition .......................................................................................... . .58
`
`9.7.1.4. Efficacy Analyses ............................................................................................ .59
`
`9.7.1.5.
`
`Safety Analyses ................................................................................................ ..6'l
`
`9.72.
`
`Statistical Power and Determination of Sample Size .......................................... ..63
`
`9.8.
`
`Changes in the Conduct of the Study or Planned Analyses ................................... ..64
`
`9.8.1.
`
`Changes in the Conduct ofthe Study ................................................................... ..64
`
`9.8.2.
`
`Changes in the Planned Analyses ........................................................................ ..66
`
`10. STUDY SUBJECTS ............................................................................................................. ..67
`
`10.1. Disposition of Subjects ............................................................................................... ..67
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048666
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 10
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`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`10.2. Protocol Deviations .................................................................................................... ..70
`
`1 1. EFFICACY EVALUA'I‘I()N ............................................................................................... ..71
`
`11.1. Data Sets Analyzed .................................................................................................... ..71
`
`11.2. Demographics and Other Baseline Characteristics ................................................ ..72
`
`l 1.2.].
`
`Subject Demographics . ........................................................................................ ..72
`
`11.2.2.
`
`Baseline Characteristics ....................................................................................... ..74
`
`11.3. Measurements of Treatment Compliance ............................................................... ..76
`
`11.4. Eflicacy Results and Tabulations of Individual Subject Data ............................... ..77
`
`11.4.1. Analysis ofEfficacy ............................................................................................. ..77
`
`11.4.1.1. Primary Efficacy Endpoint .............................................................................. ..8l
`
`11.4.1.2. Secondary Efficacy Endpoints ......................................................................... .83
`
`l 1.42.
`
`Statistical and Analytical Issues ........................................................................... .95
`
`l l 4.2.]. Adjustment for Covariates ............................................................................... ..95
`
`l 1.4.2.2. Handling ofDropouts or Missing Data ............................................................ .95
`
`ll.4.2.3. Interim Analysis and Data Monitoring ............................................................ .95
`11.4.2.4. Mulliicenter Studies .......................................................................................... .96
`
`l 1.4.2.5. Multiple Comparisons / Multiplicity ............................................................... .96
`
`l 1.4.2.6. Use of an Efficacy Subset of Subjects ............................................................. .96
`
`l l 4.2.7. Exploration of the Effects of Various Prognostic Factors on Efficacy ............ ..96
`
`11.4.2.8. Examination of Subgroups ............................................................................... .96
`
`I 1.4.3.
`
`Tabulation of Individual Response Data.............................................................. .96
`
`l1.4.4. Drug Dose, Drug Concentration, and Relationship to Response ......................... .96
`
`1 1.4.5.
`
`Drug—drug and Drug—disease Interactions ............................................................ . .97
`
`l 1.46.
`
`By—Subj ect Displays ............................................................................................. .97
`
`11.4.7.
`
`Efficacy Conclusions ........................................................................................... .97
`
`12. SAFETY EVALUATION .................................................................................................... .99
`
`12.1. Extent of Exposure ..................................................................................................... ..99
`12.2. Adverse Events ......................................................................................................... ..100
`
`.l2.2.lo Brief Surnrnary of Adverse Events .................................................................... ..lO(I)
`
`12.2.2. Display of Adverse Events ................................................................................. .101
`
`12.2.3. Analysis ofAdverse Events ............................................................................... .. 102
`
`1.2.2.3.]. Incidence of All Treatment-Emergent Adverse Events ................................. .. 102
`
`1223.2. Treatment Emergeiit Adverse Events Considered Possibly Drug~Related .... ..lO4
`
`12.2.3.3. Sunirnary of Treatment Einergent Adverse Events by Maximum liitensity.... 106
`
`ll
`
`CONFIDENTIAL INFORMATION
`
`SAL|X00048667
`
`Dr. Falk Ex. 2050
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 11
`
`

`
`Salix Pharmaceuticals, Inc.
`
`CONFIDENTIAL
`
`Encapsulated Mesa] amine Granules
`
`MPUC3004 Clinical Study Report
`
`Final: 26 October 2007
`
`12.2.4.
`
`Listing ofAdverse Events by Subject ................................................................ .107
`
`12.3. Deaths, Other Serious Adverse Events, and Other Significant
`Adverse Events ........................................................................................................ ..108
`
`12.3.1.
`
`Listing of Deaths, Other Serious Adverse Events. and Other
`
`Significant Adverse Events ................................................................................ .108
`
`12.3.1.1. Deaths .......................................................................