CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
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`208745Orig1s000
`
`STATISTICAL REVIEW(S)
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`

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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N
`CLINICAL STUDIES
`
`NDA #:
`Supplement #:
`Drug Name:
`Indication(s):
`Applicant:
`Dates:
` Submission date
` Primary review
` PDUFA V
`Review Priority:
`
`208,745
`Original
`Truelance® (Plecanatide)
`Chronic Idiopathic Constipation (CIC)
`Synergy Pharmaceuticals Inc.
`
`01/29/2016
`09/29/2016
`01/29/2017
`Standard
`
`Biometrics Division:
`Statistical Team:
` Reviewers
` Concurring Reviewer
`
`Division of Biometrics 3
`
`Shahla Farr, M.S.
`Yeh-Fong Chen, Ph.D.
`
`Division of Gastroenterology and Inborn Errors Products
`
`Medical Division:
`Clinical Team:
`Lesley Hanes, MD
` Reviewer
`Laurie Muldowney, MD
` Team Leader
`Maureen Dewey, MPH
` Project Manager
`\\CDSESUB1\evsprod\NDA208745\208745.enx
`EDR Locations:
`Keywords: NDA review, clinical study
`
`Reference ID: 4006569
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`

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`Table of Contents
`EXECUTIVE SUMMARY ....................................................................................................................................3
`INTRODUCTION ..................................................................................................................................................3
`2.1
`OVERVIEW AND BACKGROUND .........................................................................................................................4
`2.2
`DATA SOURCES .................................................................................................................................................5
`2.3
`DATA AND ANALYSIS QUALITY ........................................................................................................................5
`STATISTICAL EVALUATION ...........................................................................................................................5
`3.1
`DESCRIPTION OF BOTH STUDIES........................................................................................................................6
`3.1.1
`Study Objectives........................................................................................................................................6
`3.1.2
`Study Design .............................................................................................................................................6
`3.1.3
`Primary and Secondary Endpoints...........................................................................................................7
`3.1.4
`Analysis Population..................................................................................................................................7
`3.1.5
`Imputing Missing Values and Early Terminations ...................................................................................8
`3.2
`STATISTICAL METHODS.....................................................................................................................................9
`3.2.1
`Determination of Sample Size...................................................................................................................9
`3.2.2
`Controlling for Multiplicity of Endpoints .................................................................................................9
`3.3
`STUDY SPD304203-00....................................................................................................................................11
`3.3.1
`Patients’ Disposition and Discontinuation.............................................................................................11
`3.3.2
`Demographics and Baseline Characteristics - Study SPD304203-00 ...................................................14
`3.3.3
`Analysis of the Primary Efficacy Endpoint.............................................................................................15
`3.3.4
`Analysis of the Sensitivity .......................................................................................................................17
`3.3.5
`Analysis of the Secondary Efficacy Endpoint .........................................................................................18
`3.4
`STUDY SPD304203-03....................................................................................................................................20
`3.4.1
`Subjects with Major Protocol Deviations – Study SPD304203-03 ........................................................20
`3.4.2
`Patients’ Disposition and Discontinuation – Study SPD304203-03 ......................................................21
`3.4.3
`Demographics and Baseline Characteristics for Study SPD304203-03 ................................................23
`3.4.4
`Analysis of the Primary Efficacy Endpoint.............................................................................................24
`3.4.5
`Analysis of the Sensitivity .......................................................................................................................26
`3.4.6
`Analysis of the Secondary Efficacy Endpoint .........................................................................................26
`3.5
`EVALUATION OF SAFETY.................................................................................................................................27
`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS................................................................................28
`4.1
`SUBGROUP ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT, STUDY SPD304203-00 .................................28
`4.2
`SUBGROUP ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT, STUDY SPD304203-03 .................................28
`4.3
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION* .........................................................................................29
`4.4
`OTHER SPECIAL/SUBGROUP POPULATIONS .....................................................................................................29
`SUMMARY AND CONCLUSIONS...................................................................................................................29
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`1
`2
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`3
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`4
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`5
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`Reference ID: 4006569
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`1 EXECUTIVE SUMMARY
`
`The sponsor has submitted the results of two identical, Phase 3, multicenter, randomized double-
`blind, placebo-controlled, parallel-group studies (Study SPD304203-00 and Study SPD304203-
`03) to support the efficacy of Truelance® (Plecanatide) for the indication of Chronic Idiopathic
`Constipation (CIC).
`
`The summaries of results for both pivotal studies are as follows:
`
`Study SPD304203-00
`Difference between Plecanatide 3 mg and Placebo = 10.6%
`95% CI for the difference (6.0%, 15.2%)
`
`Study SPD304203-03)
`Difference between Plecanatide 3 mg and Placebo =7.5%
`95% CI (2.6%, 12.5%)
`
`After thorough evaluation and clarifications with the sponsor, the statistical review team
`concluded that results of the submitted two studies are statistically significance and can be used to
`support Plecanatide’s efficacy for the indication of Chronic Idiopathic Constipation (CIC) in
`adults.
`
`2 INTRODUCTION
`(Descriptions in this section are extracted from the sponsor’s clinical study report)
`
`Plecanatide (SP-304) is a peptide discovered, synthesized, and patented by Synergy
`Pharmaceuticals Inc. (hereafter referred to as Synergy) for treating patients with idiopathic or
`functional constipation.
`
`The sponsor noted in the submission that idiopathic or functional constipation is a common
`disorder that affects approximately 15% of the population of the United States (US), depending
`on demographic factors and the definition used. Internationally, similar prevalence rates have
`been observed in most geographic areas. The sponsor emphasized that although laxatives can be
`used to relieve constipation, chronic use of laxatives is often inappropriate, and may lead to side
`effects, such as dependency and progressive tolerance, electrolyte imbalance, and, for the
`anthraquinones, melanosis coli. In addition, stimulant laxatives may damage the myenteric
`plexus, resulting in cathartic colon. Laxatives available over the counter are, in general, approved
`for episodic and not chronic use.
`
` Therefore, the results are reported, mainly, for the 3 mg plecanatide.
`
`2.1 Overview and Background
`The sponsor has submitted two similar Phase 3, multicenter, randomized double-blind, placebo-
`controlled, parallel-group studies (Study SPD304203-00 and Study SPD304203-03) for duration
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`3
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`Reference ID: 4006569
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`(b) (4)
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`of 12 weeks to assess the safety and efficacy of Plecanatide (3 mg and 6 mg) for the indication of
`Chronic Idiopathic Constipation (CIC). Table 1 lists a brief description of the two studies.
`
`
`
`Study
`SPD304203-00
`
`.
`
`Proportion of durable
`overall CSBM
`responders over the
`12-week
`
`Cochran-Mantel-
`Haenszel (CMH)
`test stratified by
`gender
`
`Secondary
`° Change from baseline in
`frequency rate of CSBMs and
`SBMs:
`- Change from baseline in stool
`consistency based upon the
`BSFS:
`
`' Change from baseline in
`Staining Score:
`' Treatment Satisfaction:
`
`- Patient reported symptoms
`associated with constipation in
`the Dail S
`'.
`
`
`
`
`Table 1: Brief Descri n tion of the Phase 3 Efficac Studies
` Study # Treatment Endpoints
`
`Arm/ Sample
`Size
`3.0 mg J’ 471
`6.0 mg/ 456
`Placebo/ 467
`
`Study
`SPD304203-03
`
`3.0 mg / 469
`6.0 mg! 471
`Placebo/ 469
`‘ MC: Milli-center, It randomized, DB: double—blind, PG: parallel group, PC: placebo controlled
`
`Same as Study 00.
`above
`
`Same as Study 00. above
`
`The statistically-relevant changes to the protocol were added in Protocol version 4.0, dated 10
`April 2015 as follows:
`
`0 Changes to the statistical section of the protocol included use of MRA as the primary
`method for imputation of missing data and replaced MRA in the list of sensitivity analyses
`with observed case (originally planned as the primary method).
`
`0 Re-organized secondary endpoints into secondary and additional and changed terminology
`from key secondary to secondary (these changes are described later in the body of this
`review).
`
`0 No difference could be detected when the efficacy of the 3 mg dose was compared to the 6
`mg. So, in a mid-cycle communication with the sponsor (dated July 11, 2016),
`(m4)
`
`0 There had been some issues regarding the data integrity with
`
`(m4)
`
`(m4)
`
`(am) as these sites have had previous Agency enforcement
`action or warning letters. For that reason, we recommended that patients who were
`enrolled in these study sites be removed from the primary and secondary efficacy analysis
`for study SP304203-03, as well as the safety analyses. The applicant agreed to remove the
`8 patients as requested. On August 5, 2016 Synergy (the applicant) sent summery tables
`with the mopatients removed.
`
`During the review cycle, we asked the sponsor to re-analyze the primary endpoint by treating
`patients who had 4 or more days of missing data in a week as non—responders for that week (i.e.,
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`worst case approach). We also asked the sponsor to provide the analyses based on patients’ actual
`number of observed bowel movements when they had more than 3 days of non-missing data in a
`week.
`
`2.2 Data Sources
`In this report, we reviewed the applicant’s clinical study reports, datasets, clinical summaries, and
`proposed labeling. The submission was submitted in semi-eCTD format and was entirely
`electronic. Both SDTM and analysis datasets (ADaM) were submitted. The applicant supplied all
`data electronically as SAS transport files and can be found in the CDER electronic document
`room (EDR):
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`\\CDSESUB1\evsprod\NDA208745\208745.enx
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`The dataset that contains the primary endpoint is: ADRESP.XPT for both studies.
`
`2.3 Data and Analysis Quality
`In Study sp304203-00, after database lock on 09 Jun 2015, the Sponsor noted a data discrepancy
`for Patient 652-101. This patient had an adverse event (AE) of fecal incontinence recorded, but
`the reason for discontinuation was recorded as severe diarrhea with no corresponding entry on the
`AE page. To ensure accurate tabulation of the event, the Sponsor elected to revise the recorded
`AE from fecal incontinence to severe diarrhea. This was accomplished via (i) database unlock, (ii)
`the standard query method to the site and (iii) database relock. The specific data changes were (i)
`addition of the AE of severe diarrhea, (ii) indication that the cause of early withdrawal was the
`AE of severe diarrhea, (iii) deletion of the AE of fecal incontinence to avoid double-counting of
`the same event.
`
`No other changes to any data were made during database unlock on 22 Oct 2015. After database
`relock on 27 Oct 2015, the tabulation of patients who discontinued therapy due to diarrhea now
`correctly included Patient 652-101.
`
`The reviewer found the quality and integrity of the submitted data acceptable for the efficacy
`analyses.
`
`3 STATISTICAL EVALUATION
`
`The objectives, study design, primary and secondary efficacy endpoints, the definition of analysis
`populations and statistical methodology were similar in both clinical trials. Therefore, in this
`review, these studies are described together. The detailed efficacy analysis results for each study
`are reported separately.
`
`3.1 Description of Both Studies
`
`3.1.1 Study Objectives
`The primary objective of both studies was to evaluate the efficacy and safety of 3 mg and 6 mg of
`plecanatide administered once daily (QD) for 12 weeks in a population of patients with CIC.
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`The secondary objectives of these studies were to evaluate the effect of 3 mg and 6 mg
`plecanatide on secondary efficacy endpoints including frequency of spontaneous (SBM) and
`complete spontaneous bowel movements (CSBMs), stool consistency, straining, treatment
`satisfaction, and abdominal symptoms associated with constipation.
`
`3.1.2 Study Design
`The studies were designed as randomized, 12-week, multicenter, double-blind, parallel group,
`placebo-controlled in patients with chronic idiopathic constipation (CIC).
`
`Male and female patients who met the protocol’s criteria for CIC, based on a modification of
`Rome III criteria and who were between the ages of 18 and 80 years (inclusive) were screened for
`enrollment. Eligible patients did not have structural or post-surgical gastrointestinal (GI)
`disorders, irritable bowel syndrome (IBS), other active GI disease, or other chronic diseases that
`could cause constipation or otherwise interfere with the assessments conducted in this study.
`
`When the first set of required screening evaluations and washouts (washout of a prohibited
`concomitant medication or stabilization of a medical condition existing before the Pre-Treatment
`Period) was completed, patients who remained eligible were given an electronic hand-held device
`(EHD) in order to complete two weeks of daily diary entries as part of a Pre-Treatment EHD
`Screening assessment. Patients completed daily Pre-Treatment Period, daily assessments of
`bowel movements (BMs) (Daily BM Diary) and symptoms (Daily Symptom Diary) using the
`EHD and also recorded the amount of rescue medication (Dulcolax® 5 mg tablets, the only rescue
`medication allowed for the study) taken.
`
`To remain eligible during the Screening Period, patients had to complete at least 6 of the 7 days of
`EHD entries each week during the 2-week Pre-Treatment assessment. During the Treatment
`Period, patients who completed less than 4 days of EHD entries in any given week were
`considered a treatment failure for that week. A patient was considered compliant and evaluable
`for the day if he or she completed the BM Diary for that day up to and including the RM
`questions. Patients were NOT allowed to enter data retrospectively in the next day.
`
`Patients were required to have < 3 CSBMs, no more than 2 days of RM use, and completion of 6
`of the 7 required daily EHD entries (among other criteria) in each of the two Pre-Treatment weeks
`to be eligible for participation.
`
`Patients who were still eligible at the end of the Screening Period were stratified by gender then
`randomized in a 1:1:1 ratio to one of the following three treatment groups: 3 mg plecanatide, 6
`mg plecanatide, or placebo on Day 1 of the Treatment Period. They received their assigned study
`drug on the day of randomization (Day 1 of Week 1) and took their first dose at the clinical site.
`
`Patients continued to take a single oral dose of study drug once daily for 12 weeks. At Weeks 4,
`8, and 12 (each ± 3 days), patients returned to the clinic to undergo safety and efficacy
`assessments.
`
`At the end of the 12 weeks of study drug administration (±3 days), patients returned to the clinical
`site for End of Treatment (EOT) safety and efficacy assessments. At the end of the 2-week Post-
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`Treatment Period, they returned for End of Study (EOS) efficacy and safety assessments. Patients
`continued to complete daily EHD diaries throughout the Treatment and Post-Treatment Periods.
`
`3.1.3 Primary and Secondary Endpoints
`The primary efficacy endpoint was the proportion of patients who were durable overall CSBM
`responders over the 12-week Treatment Period.
`
`A CSBM weekly responder was defined as a patient who had ≥ 1 CSBM for that same week. An
`overall CSBM responder was defined as a patient who was a weekly responder for at least 9 of
`the 12 treatment weeks, and a durable overall CSBM responder was also a weekly responder in at
`least 3 of the last 4 weeks.
`
`Secondary efficacy endpoints included:
` Change from baseline in frequency rate of CSBMs and SBMs
` Change from baseline in stool consistency based upon the BSFS
` Change from baseline in Straining Score
` Treatment satisfaction
` Patient reported symptoms associated with constipation in the Daily Symptom Diary
`
`3.1.4 Analysis Population
`The following patient populations were assessed for the study:
`
`Safety Population: All randomized patients who received at least one dose of the study drug.
`Patients were to be analyzed according to the treatment received. All safety analyses were based
`upon the Safety Population.
`
`Intent-to-Treat (ITT) Population: All unique patients who were randomized into the study.
`Patients were analyzed according to their randomized treatment. This was the main population for
`assessment of efficacy.
`
`Per Protocol (PP) Population: All patients in the ITT Population who completed the 12-week
`Treatment Period or discontinued from study treatment due to reasons of AE(s) or lack of efficacy
`(insufficient therapeutic response) were treatment compliant and had no major protocol
`violations. Decisions regarding exclusion from the PP analysis were made prior to unblinding the
`database. All duplicate patients (index and non-index) were removed from the PP population as
`major protocol violators.
`
`3.1.5 Imputing Missing Values and Early Terminations
`The primary method for imputation of missing diary data was the mean replacement approach
`(MRA).
`
`For the responder analyses, patients who had fewer than four complete diary days were
`considered “non-responders” for that week. For this indication (CIC) the diary was considered
`complete for the day if the patient had entered at least one Daily BM Diary including RM use, or
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`Daily Symptom Diary entry. If a patient had between 4 and 6 assessments (inclusive) in a week,
`the calculations were based on a mean replacement approach (MRA). Using MRA, when diary
`data were missing in a week with partial data, the calculation of the overall weekly CSBM /SBM
`rate during a given week was seven times the number of CSBMs / SBMs divided by the number
`of days the patient reported bowel habits data. Patients with no assessments in a week were left as
`missing in the linear mixed model and analysis of covariance (ANCOVA).
`
`For secondary efficacy endpoints based on a change from baseline, a mean replacement approach
`(MRA) was applied to missing data. Specifically for BMs, when diary data were missing in a
`week with partial data, for the calculation of the overall weekly CSBM/SBM rate during a given
`week, the Sponsor multiplied seven by the number of CSBMs/SBMs divided by the number of
`days the patient reported bowel habits data. In an IR we requested the Sponsor to recalculate these
`numbers without multiplication by 7. However, if a patient had less than four diary entries in a
`week, the entire week was set to missing. For stool consistency and straining scores, any missing
`diary entry in a week did not contribute to either the numerator or denominator in computing the
`average score for the week, i.e., the weekly scores equaled the total of the BSFS or straining
`scores reported for the week divided by the number of scores reported for that week; however, if a
`patient had less than four diary entries in a week, the entire week was set to missing for the BSFS
`or straining score. Patients with no assessments in a week were left as missing in the linear mixed
`model (i.e., missing weekly data were not imputed) under the assumption that the weekly data
`were missing at random (MAR).
`
`For assessing Change from Baseline, the sponsor used a linear mixed-effects model or an analysis
`of covariance (ANCOVA). Patients with no assessments in a week were left as missing in these
`models. Additional sensitivity analyses may have been performed to test the assumption that
`missing weekly data were MAR.
`
`Sensitivity analyses based on alternative missing diary data imputation methods (such as the
`Multiple Imputation [MI], Observed Cases [OC], and Last Observation Carried Forward [LOCF]
`methodologies) were performed on the primary endpoint and the CSBM weekly responder rates
`by week over the 12-week Treatment period.
`
`The sponsor states that the patients who withdrew after randomization were not replaced.
`However, it is not clear whether these subjects were coded as non-responders.
`
`3.2 Statistical Methods
`
`3.2.1 Determination of Sample Size
`The planned sample size for this study was based on results of the previously completed large,
`multicenter, 12-week dose ranging study of plecanatide in patients with CIC and on consideration
`of overall safety exposure requirements. The percentage of overall responders used for the
`calculation was based only on information regarding the current day’s symptoms provided by the
`patient (i.e., “historic” data provided for a previous- day were excluded).
`
`The power calculation assumes that the 6 mg plecanatide overall responder rate was the same as
`seen in the 3 mg plecanatide dose group; 16.9% response rate for each plecanatide arm and 9.4%
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`for placebo. Using these assumptions, and based on a chi-square continuity-corrected test with the
`intention of providing approximately 90% power at 5% significance level, enrollment of at least
`450 patients per treatment arm was required.
`
`The efficacy analyses were based on the ITT Population and a secondary analysis was also
`performed based upon the PP Population, to assess the sensitivity of the analysis to the choice of
`analysis set.
`
`The primary efficacy endpoint was based on an analysis of the durable overall CSBM responder
`rates using a Cochran-Mantel-Haenszel (CMH) test stratified by gender. For each plecanatide
`group, the proportion of durable overall CSBM responders was compared to the proportion in the
`placebo group using the CMH test stratified by gender. The number and percentage of durable
`overall CSBM responders for each treatment group (and 95% confidence intervals [CI]), the
`difference in responder rates between each plecanatide group and the placebo group (and 95%
`CIs), and the two-sided p-value associated with the above CMH test were presented period. The
`weekly responder rate by week was analyzed using a separate CMH test, stratified by gender.
`
`3.2.2 Controlling for Multiplicity of Endpoints
`Control of family-wise type I error was applied to two sets of hypotheses—one for testing
`plecanatide 3.0 mg versus placebo and the other for testing plecanatide 6.0 mg versus placebo.
`
`The Holm-based tree-gatekeeping procedure was applied to p-values adjustment to control the
`family-wise Type I error rate at 5% (2-sided) by taking into account multiple doses and multiple
`primary and secondary endpoints. The hypotheses associated with the primary and secondary
`variables for efficacy claim were grouped into the following hierarchical families:
`
`1.
`2.
`
` Primary efficacy endpoint for the 6 mg dose group test at α =0.05 level
` Primary efficacy endpoint for the 3 mg dose group and the following secondary efficacy
`endpoints for the 6 mg dose group:
`
` Change from baseline over the 12-week treatment period in CSBM
`frequency rate
` Change from baseline over the 12-week treatment period in stool
`consistency
`The three individual hypotheses within this step were tested using an overall type I error rate
`of 0.05 by means of a Holm procedure to control for multiple parameters within this step.
`
`3. The following secondary efficacy endpoints for the 6 mg dose group:
`
` Change from baseline over the 12-week Treatment Period in SBM
`frequency rate
` Time to first SBM
` Change from baseline over the 12-week Treatment Period in straining score
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`The three individual hypotheses within this step were tested using an overall type I error rate
`of 0.05 by means of a Holm procedure to control for multiple endpoints within this step.
`
`4. The following efficacy endpoints for the 3 mg dose group:
`
` Change from baseline over the 12-week Treatment Period in CSBM
`frequency rate
` Change from baseline over the 12-week Treatment Period in stool
`consistency
`
`The tow individual hypotheses within this step were tested using an overall type I error rate of
`0.05 by means of a Holm procedure to control for multiple endpoints within this step.
`
`5. The following secondary efficacy endpoints for the 3 mg dose group:
`
` Change from baseline over the 12-week Treatment Period in SBM
`frequency rate
` Time to first SBM
` Change from baseline over the 12-week Treatment Period in straining score
`
`The three individual hypotheses within this step were tested using an overall type I error rate
`of 0.05 by means of a Holm procedure to control for multiple endpoints within this step.
`
`6. The following secondary efficacy endpoints for the 6 mg dose group:
`
` Percentage of patients with SBM within 24 hours of the first dose
` Percentage of patients with CSBM within 24 hours of the first dose
` Treatment satisfaction
`
`The three individual hypotheses within this step were tested using an overall type I error rate
`of 0.05 by means of a Holm procedure to control for multiple endpoints within this step.
`
`7. The following secondary efficacy endpoints for the 3 mg dose group:
`
` Percentage of patients with SBM within 24 hours of the first dose
` Percentage of patients with CSBM within 24 hours of the first dose
` Treatment satisfaction
`
`The three individual hypotheses within this step were tested using an overall type I error rate of
`0.05 by means of a Holm procedure to control for multiple endpoints within this step.
`Following this multiple comparison procedure, progression to the next step(s) only occurred if all
`individual hypotheses within a step were rejected and the previous step(s) were all rejected at the
`step-specific overall significant level.
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`If any hypothesis within a step was not rejected, the hypothesis tests corresponding to all
`subsequent steps were considered not statistically significant.
`
`3.3 Study SPD304203-00
`This Study started on 03 Dec 2013, ended on 23 Apr 2015and was conducted in a total of 164
`sites (153 in US and 11 Canada).
`
`Table 2 summarizes the subjects with major protocol deviations for Study SPD304203-00.
`
`Table 2: Subjects with Major Protocol Deviations - Study SPD304203-00
`
`Source: Sponsor's Study Report
`
`As it is seen in Table 2, a high number of subjects had major deviations from the protocol. A
`total of 69 subjects (34.7%) were duplicates (were not included in the ITT population); 58
`subjects (29.1%) did not meet the criteria for randomization; 28 (14.1%) errors were made in
`dispensing the drug.
`
`3.3.1 Patients’ Disposition and Discontinuation
`A total of 1394 patients were enrolled in the study; of these, 96.8%, 96.2%, and 96.7% were
`randomized to the placebo, 3 mg plecanatide, and 6 mg plecanatide groups, respectively. Five
`(0.4%) randomized patients were not treated.
`
`Two patients were inadvertently mis-randomized during this time period; one was due to human
`error and the other one was due to late detection of a programming error. During the course of
`this study, 69 subjects were identified as having study participation at more than one site and/or in
`another plecanatide study; these patients were considered to be duplicate patients. For each such
`instance of participation or attempted participation in one or more studies, the patient was
`assigned a unique, study-specific, patient identifier; thus a single individual who was classified as
`a duplicate patient was represented under more than one unique patient identifier in one or more
`studies. Duplicate patients were identified as such in the patient listings and were counted only
`once in the current ITT Population.
`
`Nine patients from the randomized population received study treatment which was inconsistent
`with their planned treatment assignment .Seven of the nine incidents occurred at one site where a
`new coordinator failed to follow proper drug kit assignment instructions.
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`The All Randomized Population reflects the planned treatment group assignments (n = 467
`placebo, 471 plecanatide 3 mg, and 456 plecanatide 6 mg, respectively). Five patients did not
`receive drug following randomization; three were in the placebo group and two in the 6 mg
`plecanatide group. The safety population reflects the actual treatment received i.e., not including
`patients not dosed and adjustments for actual treatment received (n = 458 placebo, 474
`plecanatide 3 mg, and 457 plecanatide 6 mg, respectively).
`
`Table 3 shows the number of subjects that were planned, screened and subjects who completed
`the study as a whole and for each treatment arm for study sp304203-00.
`
`Table 3: Number of Subjects - Study SPD304203-00
`Planned
`1350
`Screened
`2864
`Randomized (including duplicate patients)
`1394
`3 mg
`471
`Completed Treatment (EOT, Week 12)
`1153
`3 mg
`390
`Completed Study (EOS, Week 14)
`1140
`3 mg
`384
`
`Placebo
`385
`
`Placebo
`467
`
`Placebo
`388
`
`6 mg
`456
`
`6 mg
`375
`
`6 mg
`371
`
`Reviewer's Notes: There were discrepancies in the total number of sites reported by the Sponsor
`throughout the Study Report.
`
`A total of 1394 patients were randomized and 1389 patients received at least one dose of study
`drug (Safety Population, including duplicate patients) at 164 clinical sites in the US and Canada.
`In the Synopsis of the Study Report, under "Study Centers" it is reported that a total of 180 sites
`in US and Canada were planned, however, the actual number of active sites was183 of which 164
`randomized patients (153 US, 11 Canada). On Page 22 of 148 of the study report under section 6,
`it says: "This study was conducted at 183 clinical sites in the United States of America (USA) and
`Canada". However, 39 of these sites had initiated, but no patients were randomized. But,183-
`39=144 and not164. Table 4 shows the disposition of the subjects.
`
`Reference ID: 4006569
`
`12
`
`

`

`Table 4: Disposition of Subjects (Includes duplicate patients) - Study SPD304203-00
`
`
`
`Source: Sponsor's Table 8 in the Study Report
`
`Reviewer's Note: It should be noted that a high number of subjects withdrew from the study
`during the treatment Phase (around 17%). However, the number and proportion of these subjects
`were similar in the three treatment groups.
`
`Figure 1 shows the disposition of subjects for Study SPD304203-00
`
`13
`
`Reference ID: 4006569
`
`

`

`Figure 1: Disposition of Subjects - Study SPD304203-00
`
`Source: Sponsor's Study Report
`
`3.3.2 Demographics and Baseline Characteristics - Study SPD304203-00
`Patients ranged between 79% to 82.1% female; 45.0 year to 46.4 year mean age; 66.7% to 71.5%
`White/Caucasian and 23.9% to 28.5% Black/African American for race; 24.7% to 29.3%
`Hispanic or Latino ethnicity; and mean BMI 28.07 to 28.16 (kg/m2).
`
`Four hundred fifty two patients comprised the Intent-to-Treat (ITT) placebo group population
`with 453 and 441 patients, respectively, making up the ITT plecanatide 3 mg and 6 mg
`population.
`
`Table 5 shows the demographic and baseline characteristics