`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`203441Orig1s000
`
`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
`
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`S T A T I S T I C A L R E V I E W A N D E VA L U A T I O N
`CLINICAL STUDIES
`
`NDA/BLA #:
`Supplement #:
`Drug Name:
`Indication(s):
`Applicant:
`
`Date(s):
`
`NDA 203-441
`
`GATTEX® (teduglutide) 0.05 mg/kg/day powder for subcutaneous injection
`The treatment of adult patients with Short Bowel Syndrome (SBS)
`
`NPS Pharmaceuticals, Inc.
`Stamp Date: November 30, 2011
`PDUFA Goal date: December 30, 2012
`Standard with Major Amendment (13 month review cycle)
`
`Review Priority:
`
`
`Biometrics Division:
`Division of Biometrics III
`Statistical Reviewer:
`Behrang Vali M.S.
`Concurring Reviewers: Mike Welch Ph.D.
`
`
`Medical Division:
`Division of Gastroenterology and Inborn Errors Products
`MO: John Troiani, M.D.
`MOTL and CDTL: Ruyi He, M.D.
`Project Manager:
`Matthew C. Scherer M.B.A.
`
`
`Keywords: NDA review, Clinical Studies
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`Clinical Team:
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`Reference ID: 3225953
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`3
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`TABLE OF CONTENTS
`1 EXECUTIVE SUMMARY .................................................................................................................................5
`2
`INTRODUCTION ...............................................................................................................................................6
`2.1
`OVERVIEW......................................................................................................................................................6
`2.2
`DATA SOURCES ..............................................................................................................................................7
`STATISTICAL EVALUATION ........................................................................................................................7
`3.1
`DATA AND ANALYSIS QUALITY .....................................................................................................................8
`3.1.1
`CL-0600-004..........................................................................................................................................8
`3.1.2
`CL-0600-020..........................................................................................................................................8
`3.2
`EVALUATION OF EFFICACY ............................................................................................................................8
`3.2.1
`Study Design and Endpoints..................................................................................................................8
`3.2.2
`Statistical Methodologies.....................................................................................................................15
`3.2.3
`Patient Disposition, Demographic and Baseline Characteristics........................................................18
`3.2.4
`Results and Conclusions ......................................................................................................................24
`3.3
`EVALUATION OF SAFETY..............................................................................................................................36
`3.4
`BENEFIT-RISK ASSESSMENT.........................................................................................................................36
`4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .............................................................................36
`4.1
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ........................................................................................36
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................37
`SUMMARY AND CONCLUSIONS ................................................................................................................37
`5.1
`STATISTICAL ISSUES.....................................................................................................................................37
`5.2
`COLLECTIVE EVIDENCE................................................................................................................................37
`5.3
`CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................38
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`5
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`Reference ID: 3225953
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`LIST OF TABLES
`Table 1 Summary Information for Relevant Clinical Trials ..........................................................................................7
`Table 2 Criterion Values for Graded Response ...........................................................................................................12
`Table 3 Disposition CL-0600-004...............................................................................................................................19
`Table 4 Demographic and Baseline Characteristics CL-0600-004..............................................................................20
`Table 5 Disposition CL-0600-020...............................................................................................................................22
`Table 6 Demographic and Baseline Characteristics CL-0600-020..............................................................................23
`Table 7 Number and Percent of Patients by Graded Response CL-0600-004.............................................................24
`Table 8 Number and Percent of Patients with Binary Response CL-0600-004...........................................................25
`Table 9 Number and Percent of Patients with at least 1-day Reduction in weekly PN Usage CL-0600-004..............26
`Table 10 Change from Baseline in Weekly PN kilojoules CL-0600-004....................................................................26
`Table 11 Change from Baseline in Weekly PN Volume CL-0600-004.......................................................................27
`Table 12 Change from Baseline in Plasma Citrulline CL-0600-004 ...........................................................................28
`Table 13 Number and Percent of Patients with Binary Response CL-0600-020.........................................................30
`Table 14 Percent Change from Baseline to Last Dosing Visit in Weekly PN Volume CL-0600-020.........................32
`Table 15 Duration of Response CL-0600-020.............................................................................................................33
`Table 16 Patients with 20% or 2L Reduction in PN Volume at Week 20, Maintained to Week 24 CL-0600-020 .....33
`Table 17 Patients who stop PN Usage CL-0600-020 ..................................................................................................34
`Table 18 Number and Percent of Patients by Graded Response CL-0600-020 ...........................................................34
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`Reference ID: 3225953
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`LIST OF FIGURES
`Figure 1 Study Diagram CL-0600-004..........................................................................................................................9
`Figure 2 Study Diagram CL-0600-020........................................................................................................................13
`Figure 3 Disposition CL-0600-004..............................................................................................................................19
`Figure 4 Disposition CL-0600-020..............................................................................................................................21
`Figure 5 Mean (± SE) PN Weekly Volume by Treatment Group – CL-0600-004/CL-0600-005 ...............................29
`Figure 6 Mean (± SE) PN Weekly Volume by Treatment Group – CL-0600-020/CL-0600-021 ...............................35
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`Reference ID: 3225953
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`1 EXECUTIVE SUMMARY
`
`There was a sufficient level of evidence to support an efficacy claim for GATTEX®
`(teduglutide), and the claims currently reflected within the applicant’s submitted product label
`were verified during this NDA review. With further motivation under the current public health
`circumstances in which Short Bowel Syndrome is a rare, serious and life-threatening condition
`with an unmet medical need, the reviewer supports the approval of teduglutide for the treatment
`of adult patients with this condition.
`
`There were no major statistical issues that impacted the overall conclusions from the trials CL-
`0600-020 and CL-0600-004. Each study’s design was adjudicated as being adequate, and the
`applicant’s corresponding analysis plans were deemed appropriate. The change in primary
`endpoint during the conduct of trial CL-0600-004 could have possibly been an issue, however it
`ultimately was not. The premise behind this change in primary endpoint was understandable and
`acceptable. And although it would have been more ideal for the sponsor to have changed their
`endpoint prior to study enrollment, the decision was conducted with an independent and blinded
`team of consultants. As seen in section 3.2.4.1, this change in endpoint made no impact on the
`interpretation of this study’s conclusions.
`
`The efficacy of the 0.05 mg/kg/day teduglutide dose, for which the applicant is pursuing
`labeling, was principally demonstrated in trial CL-0600-020. The primary endpoint, Binary
`Response, and almost all secondary endpoints were significantly in favor of teduglutide.
`Consequently, results from trial CL-0600-020 are viewed positively as the formal basis for an
`efficacy claim to be reflected in the product’s label. In trial CL-0600-004, the 0.05 mg/kg/day
`teduglutide dose showed a numerical advantage over Placebo for both Binary and Graded
`Response endpoints, and results from trial CL-0600-004 are viewed as supportive. With a
`sustained efficacy profile during the extension studies and with the Gastrointestinal Drug
`Advisory Committee’s concurrence regarding the clinical meaningfulness of the Binary
`Response endpoint, overall there is a sufficient level of evidence to support an efficacy claim for
`teduglutide.
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`Reference ID: 3225953
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`2 INTRODUCTION
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`2.1 Overview
`
`Pursuant to Section 505(b)(1) of the Federal Food, Drug and Cosmetic Act and in accordance
`with Title 21, Part 314 of the Code of Federal Regulations, NPS Pharmaceuticals, Inc. submitted
`the New Drug Application (NDA) for GATTEX® (teduglutide) on November 30, 2011. The
`active pharmaceutical ingredient in GATTEX powder [delivery by daily subcutaneous injection]
`is teduglutide which is a human recombinant analog of glucagon-like peptide-2 (GLP-2). This is
`the first prescription product to have teduglutide as its active pharmaceutical ingredient thereby
`making it a New Molecular Entity (NME). Effective on May 27, 1999, GATTEX has officially
`undergone clinical development under IND 58,213 in patients with short bowel syndrome (SDS),
`and has been developed specifically to establish safety and efficacy in this patient population.
`Patients with SDS have a deficiency in the absorption of fluid and nutrients within the small
`intestine. As a result SDS patients are dependent on parenteral nutrition (PN) to stay alive,
`however long term PN usage is shown to be dangerous for these patients. GATTEX is utilized to
`improve intestinal absorption of fluid and nutrients, and decrease the need for total parenteral
`nutrition. Currently there are no FDA-approved treatment options for patients with SDS,
`consequently this serious and life threatening condition remains as one with an unmet medical
`need.
`
`NPS Pharmaceuticals, Inc. obtained permission from the Division of Gastroenterology and
`Inborn Errors (DGIEP) to file their submission to facilitate a rolling review, and the final
`component of their rolling submission (which officially started the original PDUFA clock) was
`delivered on November 30, 2011. The original review cycle established by DGIEP was a
`standard 10 month cycle; however this was later amended to being a 13 month review cycle in
`order to aid its Advisory Committee meeting. The application also qualified for Orphan
`Exception under section 736(a)(1)(E) of the Federal Food, Drug and Cosmetic Act, and NPS
`Pharmaceuticals, Inc. ultimately obtained Orphan Designation from the Office or Orphan
`Products Development (OOPD) on June 29, 2000.
`
`The clinical efficacy and safety of GATTEX has been principally evaluated through two studies:
`a Phase 3, multicenter, randomized, double-blind, parallel-group placebo-controlled study
`(CL0600-020) which serves as the lone adequate and well controlled study of this clinical
`development program as per 21 CFR 314.126; and a Phase 3, multicenter, randomized, double-
`blind, parallel-group placebo-controlled study (CL0600-004) which acts as the principally
`supportive study of this clinical development program.
`
`
`Table 1 below presents information on the two relevant clinical trials contained in the
`submission.
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`Reference ID: 3225953
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`Table 1
`Summary Information for Relevant Clinical Trials
`Study
`Design
`and
`Type of
`Control
`
`Number of
`Dosed
`Subjects
`
`Patient
`Diagnosis
`
`Multicenter,
`double-blind,
`randomized,
`parallel-group,
`placebo-
`controlled
`
`teduglutide 0.05
`mg/kg along with
`matching
`placebo;
`daily;
`subcutaneous
`injection
`
`Multicenter,
`double-blind,
`randomized,
`parallel-group,
`placebo-
`controlled
`
`teduglutide 0.10
`mg/kg and 0.05
`mg/kg along with
`matching
`placebo;
`daily;
`subcutaneous
`injection
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`0.05 mg/kg: 42
`placebo: 43
`Total: 85
`
`0.10 mg/kg: 32
`0.05 mg/kg: 35
`placebo: 16
`Total: 83
`
`Male or female
`subjects with
`parenteral
`nutrition-
`dependent
`SBS
`
`Male or female
`subjects with
`parenteral
`nutrition-
`dependent
`SBS
`
`Objective(s)
`of the Study
`
`Evaluate the
`efficacy, safety,
`tolerability and PK
`of teduglutide
`compared with
`placebo in subjects
`with parenteral
`nutrition dependent
`SBS
`
`Evaluate the
`efficacy, safety,
`tolerability and PK
`of teduglutide
`compared with
`placebo in subjects
`with parenteral
`nutrition dependent
`SBS
`
`Source: Reviewer’s Table.
`
`2.2 Data Sources
`
`This NDA was submitted electronically in eCTD format via the FDA Electronic Submissions
`Gateway (ESG). Its content, including the electronic data sets and labeling information, has
`been stored in the electronic document room (EDR) at this path location:
`\\Cdsesub1\evsprod\NDA203441. Sequences 0001, 0004, 0010, and 0021 contain all the
`contents relevant for this review.
`
`For each of the two aforementioned clinical studies, the applicant’s clinical study report (CSR),
`clinical datasets and analysis datasets were reviewed. Each study’s clinical datasets were
`compliant to CDISC/SDTM v.3.1.2 standards; however, both studies utilized a non-standardized
`legacy approach for modeling the corresponding analysis data. Adequate data definition files
`and software code was also submitted for both studies.
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`
`
`Test
`Product(s);
`Regimen;
`Route
`
`Type of
`Study;
`Phase
`
`Efficacy
`and Safety;
`Phase 3
`
`
`Efficacy
`and Safety;
`Phase 3
`
`
`Study
`Identifier
`
`CL-0600-020
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`CL-0600-004
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`Duration
`of
`Treatment
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`Study
`Status;
`Type of
`Report
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`24 weeks
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`Complete;
`Full
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`24 weeks
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`Complete;
`Full
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` 3
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` STATISTICAL EVALUATION
`
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`The organization of the sub-sub-sections (and sub-sub-sub-sections if applicable) throughout
`section 3 will be made by clinical study.
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`Reference ID: 3225953
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`3.1 Data and Analysis Quality
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`3.1.1 CL-0600-004
`This study utilized Case Report Forms (CRF), and the submitted data quality and integrity
`appeared to be adequate. There were no issues in reproducing the primary analysis dataset
`(along with the numerical results presented within the CSR), in particular the primary endpoint,
`from the original data source. It was possible to verify the randomized treatment assignments,
`and the applicant submitted documentation of data quality control/assurance procedures within
`section 9.6 of their ICH E3 compliant CSR. The blinding/unblinding procedures were well
`documented within the protocol and in section 9.4.6 of their ICH E3 compliant CSR. The
`applicant’s statistical analysis plan (SAP) was finalized on April 20, 2007. The SAP was
`submitted and all relevant analysis decisions were made before unblinding. Database hard-lock
`was on July 27, 2007 with unblinding one week later on August 3, 2007.
`
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`3.1.2 CL-0600-020
`This study utilized Electronic Data Capture (EDC), and the submitted data quality and integrity
`appeared to be adequate. There were again no issues in reproducing the primary analysis dataset
`(along with the numerical results presented within the CSR), in particular the primary endpoint,
`from the original data source. It was possible to verify the randomized treatment assignments,
`and the applicant submitted documentation of data quality control/assurance procedures within
`section 9.6 of their ICH E3 compliant CSR. The blinding/unblinding procedures were well
`documented within the protocol and in section 9.4.6 of their ICH E3 compliant CSR. The
`applicant’s SAP was finalized on December 21, 2010. The SAP was submitted and all relevant
`analysis decisions were made before unblinding. Database hard-lock was on January 25, 2011
`with unblinding one week later on February 1, 2011.
`
`
`3.2 Evaluation of Efficacy
`
`3.2.1 Study Design and Endpoints
`
`3.2.1.1 CL-0600-004
`This Phase 3 efficacy and safety study was the first, in sequence, to be designed and
`subsequently executed by the applicant to ultimately support an efficacy claim to be reflected by
`the product label. CL-0600-004 was a 24-week multicenter, double-blind, randomized, parallel
`group, placebo-controlled trial which was to study two different doses of teduglutide: 0.10
`mg/kg/day and 0.05 mg/kg/day. The original protocol for this study was signed off on October
`27, 2003. The final version of this protocol, after a series of amendments, was set on September
`5, 2007. This last amendment, which occurred after enrollment was finished, was for an
`administrative change which did not affect trial conduct i.e. study treatment, duration or
`procedures. Study initiation was on May 25, 2004 while study completion was on July 6, 2007.
`Figure 1 below diagrams study CL-0600-004.
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`Reference ID: 3225953
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`Figure 1
`Study Diagram CL-0600-004
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`
`
`Source: CL-0600-004 CSR - Figure 9-1 on pg. 24.
`
`In order to establish the same relative PN baseline for all patients, the protocol specified a period
`of fluid optimization followed by stabilization prior to randomization. During optimization, a
`subject’s PN/Intravenous (I.V.) fluid volume was adjusted over one or more 48-hour periods.
`PN/I.V. was adjusted to keep urine output between 1.0 and 2.0 L/day, while the patient was
`asked to maintain their oral fluid intake at the same volume as during their previous 48-hour
`adjustment (or baseline in the case of the first adjustment). During stabilization, PN/I.V. volume
`was assessed for ‘stability’ i.e. urine output 1-2 L/day under constant oral intake. PN/I.V.
`volume at the end of stabilization was taken as the Baseline measurement for all subsequent
`efficacy assessments.
`
`After stabilization and the Baseline fluid volume assessment, subjects were randomized in a
`1:2:2 ratio to placebo, teduglutide 0.05 mg/kg/day, or teduglutide 0.10 mg/kg/day. The
`randomization was stratified by two multi-level factors/variables:
`• participation in the 72-hour nutrient absorption test (2 levels: ‘yes’, ‘no’)
`• PN at three levels of consumption [3 levels: PN consisting of IV fluid and electrolytes
`only (3-7 times weekly), PN 3-5 times weekly, and PN 6-7 times weekly].
`
`
`At that time, those subjects randomized to placebo were further randomized in a 1:1 ratio
`prospectively for possible inclusion in the 28-week, multicenter, double-blind extension study to
`assess the long term efficacy and safety (trial CL-0600-005) of the 0.05 or the 0.10 mg/kg/day
`teduglutide doses. All patients who participated in study CL-0600-004 were eligible to enroll in
`this follow-up roll-over trial.
`
`
`Within the original protocol, the following primary and secondary endpoints were pre-specified
`in the following order.
`
`Primary Endpoint: The number and percentage of subjects who demonstrated a response at
`Week 20, and who sustained that response through Week 24. Response was defined as the
`achievement of at least a 20% reduction from Baseline in weekly PN volume [measured in terms
`of Liters(L)/week]. The applicant refers to this endpoint as ‘Binary Response’.
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`Reference ID: 3225953
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`Secondary Endpoints:
`• Number and percentage of subjects with at least a 1-day reduction in weekly PN usage
`• Absolute reduction from Baseline in weekly PN kilojoules (transformed from
`kilocalories)
`• Absolute reduction from Baseline in weekly volume of PN
`• Change from Baseline in plasma citrulline at Dosing Week 24
`
`
`These secondary endpoints were deemed by the applicant as being supportive to determining the
`intensity and duration of the response to treatment with teduglutide.
`
` A
`
`•
`
` sample size of 80 randomized subjects (32 subjects in each of the teduglutide treatment groups
`and 16 subjects in the placebo group) was to provide at least 90% power to detect an increase in
`the percentage of subjects who had the protocol-defined minimum response (20% decrease for
`both Weeks 20 and 24), from 5% in the placebo treatment group to 50% in the teduglutide
`treatment groups (80% power to detect an increase to 44%). The power calculations were based
`on two-sided tests of significance using Fisher’s Exact test at α=0.05.
`
`The two teduglutide treatment groups (0.10 mg/kg/day, 0.05 mg/kg/day) were each to be
`compared to the placebo group. For the secondary efficacy analyses, all pair-wise comparisons
`were also performed. The following step-down procedure was pre-specified within the original
`protocol to be used to adjust for multiple comparisons in the analysis for the primary endpoint,
`and then, in the order previously shown, for each of the secondary endpoints:
`
`Step 1: The 0.10 mg/kg/day teduglutide group was to be compared with the placebo group using
`a two-sided test at a 0.05 significance level.
`•
`If the 0.10 mg/kg/day teduglutide group was not significantly different from the placebo
`group, no further comparisons were to be made.
`If the 0.10 mg/kg/day teduglutide group was significantly different from the placebo
`group, comparisons were to continue to Step 2.
`
`
`Step 2: The 0.05 mg/kg/day teduglutide group was to be compared with the placebo group using
`a two-sided test at a 0.05 significance level.
`•
`If the 0.05 mg/kg/day teduglutide group was not significantly different from the placebo
`group, no further comparisons were to be made.
`If the 0.05 mg/kg/day teduglutide group was significantly different from the placebo
`group, comparisons were to continue to Step 3.
`
`•
`
`
`Step 3: The 0.10 mg/kg/day teduglutide group was to be compared with the 0.05 mg/kg/day
`teduglutide group using a two-sided test at a 0.05 significance level.
`•
`If the teduglutide groups were significantly different from one another, comparisons were
`to move back to Step 1 using the next endpoint in line.
`
`
`Prior to completion of study enrollment and preparation of the SAP, NPS organized a meeting,
`on July 28, 2006, with an independent panel of expert clinicians and statisticians in order to
`discuss the statistical components of this study protocol. The expert panel present at this
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`Regulatory Expert Consultants meeting was asked to review the protocol and make
`recommendations regarding the primary endpoint. Subsequently, an expanded primary endpoint
`was developed which the consultants and NPS agreed to be of greater sensitivity and specificity
`than the originally proposed primary endpoint previously presented. It was hoped that the
`utilization of this expanded endpoint would result in greater power to detect a treatment effect
`for teduglutide in the study. This expanded primary measure assesses intensity and sustained
`durability of PN reduction, both of which were considered clinically meaningful by the
`consultants. The expanded primary measure was built on the foundation of the originally
`proposed primary measure, and thus the transition was viewed as easily supportable from a
`regulatory perspective. No study data were provided to the consultants, and the study was fully
`blinded at the time of this meeting. The protocol was officially amended (Amendment 4b) on
`June 29, 2007 to include this new primary endpoint. It is to be noted, however, that the study’s
`SAP was amended on April 20, 2007 to reflect this change, and this amendment took place prior
`to the official protocol amendment on June 29, 2007.
`
`The New Primary Endpoint was defined as follows - An ordered categorical (or graded) response
`variable that accounts for both intensity and duration of response at the end of the 24-week
`treatment period. The intensity of response relies on a reduction from baseline in weekly PN
`volume, where the protocol defined reduction is set at a minimum of 20% and a maximum of
`100%. Duration of response incorporates the responses at Weeks 16 to 20 and Weeks 20 to 24.
`Accordingly, the response variable is:
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`Reference ID: 3225953
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`It is to be noted that y1 is equivalent to the previously presented original primary endpoint.
`Values for the response criterion, y, are presented in Table 2 below.
`
`
`Table 2
`Criterion Values for Graded Response
`
`Source: CL-0600-004 Protocol (Amendment 4b) - Table 8-1 on pg. 43.
`
`As a result, the original primary endpoint, Binary Response, was demoted one level down to
`being the key secondary endpoint. The ordering of the other secondary endpoints did not
`change, and the step-down procedure to adjust for multiple comparisons also stayed as is with
`the new primary endpoint now being assessed first.
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`Reference ID: 3225953
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`Reviewer Comments:
`The premise behind this change in primary endpoint was understandable and acceptable. And
`although it would have been more ideal for the sponsor to have organized their July 2006
`meeting prior to study enrollment, the fact that it was conducted using an independent and
`blinded team of consultants results in no regulatory review issues. As will be seen in the results
`section, this change in endpoint made no impact on the interpretation of study
`results/conclusions. It can be argued that the graded response endpoint itself was actually not
`technically ordinal as the applicant purports. As an example from Table 2 above, at Weeks 20 to
`24, a value of 3 from complete PN stoppage is actually scored worse by the scoring system than
`a 4 achieved from only a 40% reduction. Many examples of this violation in ordinality can be
`found in Table 2. Nonetheless, overall the design of study CL-0600-004 was adequate, and the
`estimated sample size was validated and confirmed as appropriate.
`
`3.2.1.2 CL-0600-020
`This Phase 3 efficacy and safety study was designed and executed by the applicant after the
`completion of trial CL-0600-004. This trial served as the clinical development program’s
`adequate and well-controlled study which made it the basis for an efficacy claim to be reflected
`by the product label. CL-0600-020 was a 24-week multicenter, double-blind, randomized,
`parallel group, placebo-controlled trial whose primary objective was to confirm the efficacy of
`the teduglutide’s 0.05 mg/kg/day dose. The original protocol for this study was signed off on
`September 4, 2008. The final version of this protocol, after a few amendments, was set on
`January 14, 2010. Study initiation was on November 25, 2008 while study completion was on
`January 4, 2011. Figure 2 below diagrams study CL-0600-020.
`
`Figure 2
`Study Diagram CL-0600-020
`
`Source: CL-0600-020 CSR - pg. 6.
`
`The design and population of study CL-0600-020 was very similar to that of CL-0600-004.
`
`In order to establish the same relative PN baseline for all patients, an important part of the study
`was to establish consistency in PN/I.V. fluid management among all investigators at entry and
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`Reference ID: 3225953
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`BEST AVAILABLE COPY
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`throughout the trial. To this end, the study protocol, like that of CL-006-004, specified a period
`of fluid optimization followed by a period of stabilization and the criteria to manage fluids.
`
`During optimization, a subject’s PN/I.V. fluid volume was adjusted over one or more 48-hour
`periods. PN/I.V. was adjusted to keep urine output between 1.0 and 2.0 L/day while the patient
`was asked to maintain their oral fluid intake at the same volume as during their previous 48-hour
`adjustment (or baseline in the case of the first adjustment).
`
`During stabilization, PN/I.V. volume was assessed for ‘stability’ i.e. urine output 1-2 L/day
`under constant oral intake. PN/I.V. volume at the end of stabilization was taken as the Baseline
`measurement for all subsequent efficacy assessments. If stability was not achieved the first time
`through Stage 1 (see Figure 2 above), patients returned to the optimization phase again, followed
`again by stabilization. If stability was still not achieved, i.e. the second time through the
`sequence, the subject was not randomized or allowed to continue the trial.
`
`After stabilization is finally achieved along with the Baseline fluid volume assessment made,
`subjects were randomized in a 1:1 ratio to placebo or teduglutide 0.05 mg/kg/day. The
`randomization was stratified by one two-level factor/variable i.e. Baseline PN/I.V. fluid volume
`(≤6 L/week, >6 L/week).
`
`It is to be noted that all subjects randomized into this study were later given the opportunity to
`roll over into the currently ongoing 2-year, multicenter, open-label, un-controlled extension
`study (trial CL-0600-021) which assesses the long term efficacy and safety of the 0.05
`mg/kg/day teduglutide treatment.
`
`The following primary and secondary endpoints were pre-specified in the following order.
`
`Primary Endpoint: Binary Response i.e. the number and percentage of subjects who
`demonstrated a response at Week 20, and who sustained that response through Week 24.
`Response was defined as the achievement of at least a 20% reduction from Baseline in weekly
`PN volume.
`
`Reviewer Comments:
`It is to be noted that this primary endpoint is the same as the original primary endpoint (which
`later became the key secondary endpoint) of the CL-0600-004 study. NPS went back to utilizing
`this more simplistic endpoint as the primary endpoint for this confirmatory study. A
`Gastroenterology Drug Advisory Committee meeting regarding this marketing application was
`held on October 16, 2012, and this endpoint was deemed as clinically meaningful by all
`members of the committee.
`
`Secondary Endpoints:
`• Percent change in PN volume between baseline and last dosing visit, where the last
`dosing visit is the last scheduled visit (including early termination visits) for which there
`was at least 14 days since the previously scheduled study visit
`• Absolute change in PN volume between baseline and last dosing visit
`
`
`
`Reference ID: 3225953
`
`14
`
`

`

`• Duration of response (number of consecutive visits with at least 20% reduction)
`• Proportion of patients with at least 20% reduction or at least a 2 L reduction from
`baseline in weekly PN at Week 20 and maintained through Week 24
`• Number of subjects who stop PN altogether, and the time of stopping PN
`• Graded (or ordered categorical) response i.e. the CL-006-004 study’s new primary
`endpoint as previously described
`
`
`These secondary endpoints were premised on reductions in PN/I.V. volume or the direct effects
`of improved intestinal absorption of fluid. The applicant felt that these endpoints were clinically
`meaningful.
`
` A
`
` sample size of 86 subjects (43 subjects in the teduglutide treatment group and 43 subjects in
`the placebo group) was to provide at least 90% power to detect a difference in responder rates
`between the active and placebo arms of 35% vs. 6%, respectively. This power