CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`210875Orig1s000
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`STATISTICAL REVIEW(S)
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` U.S. Department of Health and Human Services
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` Food and Drug Administration
` Center for Drug Evaluation and Research
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` 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 V A L U A T I O N
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` C L I N I C A L S T U D I E S
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` 210875
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` Kynmobi (Apomorphine Hydrochloride Sublingual Film)
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` Acute, intermittent treatment of “OFF” episodes associated with
` Parkinson’s disease
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` Sunovion Pharmaceuticals, Inc.
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` NDA Number:
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` Drug Name:
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` Indication:
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` Applicant:
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` Dates:
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` Receipt date: March 29, 2018
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` PDUFA Goal Date: January 29, 2019
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` Review Priority:
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` Standard
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` Biometrics Division:
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` Division of Biometrics I
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` Statistical Reviewer:
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` Xiangmin Zhang, Ph.D.
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` Concurring Reviewers: Kun Jin, Ph.D., Team Leader
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` Hsien Ming Hung, Ph.D., Director
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` Medical Division:
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` Clinical Team:
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` Division of Neurology Products
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` Kenneth Bergmann, M.D., Clinical Reviewer
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` Gerald Podskalny, D.O., Team Leader
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` Eric Bastings, M.D., Deputy Director
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` William Dunn, M.D., Director
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` Project Manager:
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` Jack Dan, R.Ph.
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` Keywords: clinical studies, mixed models, NDA review
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`Reference ID: 4365433Reference ID: 4613103
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`3
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`TABLE OF CONTENTS
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`TABLE OF CONTENTS ............................................................................................................................................2
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`LIST OF TABLES.......................................................................................................................................................3
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`LIST OF FIGURES.....................................................................................................................................................4
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`1
` EXECUTIVE SUMMARY .................................................................................................................................5
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`2
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`INTRODUCTION ...............................................................................................................................................5
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`2.1 OVERVIEW......................................................................................................................5
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`2.2 DATA SOURCES...............................................................................................................5
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`STATISTICAL EVALUATION ........................................................................................................................6
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`3.1 DATA AND ANALYSIS QUALITY .......................................................................................6
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`3.2 EVALUATION OF EFFICACY..............................................................................................6
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`Study Design and Endpoints ...............................................................................................................6
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`3.2.1
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`Statistical Methodologies....................................................................................................................8
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`3.2.2
`Patient Disposition, Demographic and Baseline Characteristics.......................................................9
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`3.2.3
`Results and Conclusions ...................................................................................................................12
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`3.2.4
`3.3 EVALUATION OF SAFETY ...............................................................................................15
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`FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .............................................................................15
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`4.1 GENDER, RACE, AGE, AND GEOGRAPHIC REGION...........................................................15
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`4.2 OTHER SPECIAL/SUBGROUP POPULATIONS.....................................................................18
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`SUMMARY AND CONCLUSIONS ................................................................................................................18
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`5.1 STATISTICAL ISSUES......................................................................................................18
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`5.2 COLLECTIVE EVIDENCE .................................................................................................18
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`5.3 CONCLUSIONS AND RECOMMENDATIONS .......................................................................18
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`4
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`5
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`Reference ID: 4365433Reference ID: 4613103
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` 2
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` LIST OF TABLES
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`Table 1. The clinical study in this review .................................................................................5
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`Table 2. Patient disposition (randomized population) .............................................................9
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`Table 3. Patient demographics (mITT population) ...............................................................10
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`Table 4. Patient baseline characteristics (mITT population) ................................................11
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`Table 5. Analysis of the change from pre-dose to 30 minutes post-dose in the MDS-UPDRS
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`Part III score at Week 12 (mITT population) .........................................................13
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`Table 6. Analysis of the percentage of subjects with a subject-rated full "ON" response
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`within 30 minutes at Week 12 (mITT population) ..................................................15
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`Table 7. Subgroup analysis by gender of the change from pre-dose to 30 minutes post-dose
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`in the MDS-UPDRS Part III score at Week 12 (mITT population)........................16
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`Table 8. Subgroup analysis by age group of the change from pre-dose to 30 minutes post-
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`dose in the MDS-UPDRS Part III score at Week 12 (mITT population) ...............17
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`Table 9. Subgroup analysis by randomized dose of the change from pre-dose to 30 minutes
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`post-dose in the MDS-UPDRS Part III score at Week 12 (mITT population) .......18
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`Reference ID: 4365433Reference ID: 4613103
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` 3
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` LIST OF FIGURES
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`Figure 1. Design schematic .......................................................................................................6
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`Figure 2. Dosing paradigm .......................................................................................................7
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`Figure 3. Observed mean (± standard error) change from pre-dose to 30 minutes post-dose
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`in the MDS-UPDRS Part III score by visit and treatment (mITT population) ....12
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`Figure 4. Least square mean (± standard error) change from pre-dose to 30 minutes post-
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`dose in the MDS-UPDRS Part III score by visit and treatment (mITT population)
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`..................................................................................................................................14
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`Reference ID: 4365433Reference ID: 4613103
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` 4
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` 1 EXECUTIVE SUMMARY
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`This review described the statistical findings of Kynmobi (apomorphine hydrochloride
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`sublingual film) as an acute, intermittent treatment of “OFF” episodes associated with
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`Parkinson’s disease. The review confirmed that Study CTH-300 - a randomized, double-blind,
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`placebo-controlled, parallel-group study - in the 505(b)(2) new drug application provided
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`statistical evidence that Kynmobi is efficacious: Kynmobi is statistically better than placebo in
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`terms of the change from pre-dose to 30 minute post-dose in the Movement Disorders Society ­
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`Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III (Motor Examination) score at
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`Week 12.
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`2
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` 2.1 Overview
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` On March 29, 2018, Sunovion Pharmaceuticals, Inc. (the Applicant) submitted a 505(b)(2) new
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` drug application (NDA) for apomorphine hydrochloride sublingual film (APL-130277 under the
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` Applicant’s clinical development program) as an acute, intermittent treatment of “OFF” episodes
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` associated with Parkinson’s disease (PD). The NDA submission lists Food and Drug
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` Administration approved drug Apokyn® (NDA 021264) as the 505(b)(2) reference. The
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`Applicant submitted one clinical study in the NDA to support the efficacy claim of APL-130277.
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`This clinical study is summarized below and reviewed in Section 3.
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` INTRODUCTION
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` Table 1. The clinical study in this review
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` Study
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` Number
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` Phase and Design
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` Maintenance
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` Period
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` Study Arm
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` Study Population
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` CTH-300
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` Phase3, randomized,
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` double-blind,
`placebo-controlled,
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` parallel-group
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` 12
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` Placebo
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` Kynmobi
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` (54)
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` Male and female
` subjects ≥ 18 years
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` of age with
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` Parkinson’s disease
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` Source: statistical reviewer’s summary
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` 2.2 Data Sources
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` The electronic submission of this NDA is located at
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` \\cdsesub1\evsprod\NDA210875\0001\
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`The study reports are located at
`\\cdsesub1\evsprod\NDA210875\0001\m5\53-clin-stud-rep\535-rep-effic-safety­
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`stud\parkinsons\5351-stud-rep-contr\cth-300\
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`Reference ID: 4365433Reference ID: 4613103
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`The datasets are located at
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`\\cdsesub1\evsprod\NDA210875\0001\m5\datasets\cth-300\
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` 3 STATISTICAL EVALUATION
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` 3.1 Data and Analysis Quality
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`The data quality and analysis quality are adequate. The statistical reviewer was able to perform
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`independent review using the Applicant’s submitted datasets and confirm the Applicant’s
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`analysis results.
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`3.2 Evaluation of Efficacy
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`3.2.1 Study Design and Endpoints
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`Study CTH-300 was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 2­
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`arm, multi-center study to evaluate the efficacy, safety, and tolerability of APL-130277 in
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`patients with PD. Approximately 126 patients were planned to be enrolled; approximately 114
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`patients were planned to be randomized in a 1:1 ratio to placebo and APL-130277 groups.
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` Figure 1. Design schematic
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` Source: Figure 1 on page 26 of the clinical study report body
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`Figure 1 depicted the study design schematic of Study CTH-300. The study consisted of a dose
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`titration phase and a 12-week double-blind maintenance treatment phase. In the dose titration
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`phase, patients had up to six titration visits. The minimum titration dose was 10 mg APL­
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`130277; the maximum titration dose was 35 mg APL-130277.
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`Reference ID: 4365433Reference ID: 4613103
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` Figure 2. Dosing paradigm
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` Source: figure on page 21 of the protocol
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`Figure 2 depicted the dosing paradigm of the dose titration phase. Before each titration visit or
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`maintenance visit, patients were instructed to take their last dose of Levodopa (L-Dopa) and any
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`other adjunctive PD medication no later than midnight on the evening prior and skip their regular
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`morning does of L-Dopa or any other adjunctive PD medications on the day of the visit. During
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`each titration visit, the patients was presented to the clinic in an “OFF” state then treated with
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`APL-130277; the patient and investigator assessed whether the patient responded to the APL­
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`130277 with a full “ON” response within 45 minutes of taking APL-130277. Per the clinical
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`study protocol, a patient-assessed full “ON” is defined as “a period of time where medication is
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`providing benefit with regard to mobility, stiffness and slowness and where a patient feels he/she
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`can perform normal daily activities; AND the response is comparable to or better than their
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`normal response to PD medications prior to enrolling in the study”; an investigator-assessed full
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`Reference ID: 4365433Reference ID: 4613103
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` “ON is defined as “per clinical judgment, the period of time where the Investigator feels the
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` medication is providing benefit with regard to mobility, stiffness and slowness and the patient
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` has adequate motor function to allow them to perform their normal daily activities”. Patients who
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` achieved a full “ON” response, as assessed by the patient and investigator, within 45 minutes of
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` taking APL-130277 proceeded to randomization and the maintenance treatment phase at this
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` dose, otherwise, patients were titrated to the next dose level in the next titration visit.
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`Following the dose titration phase, patients were randomized in a 1:1 ratio to placebo and APL­
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`130277 groups and returned to the clinics at monthly interval during the 12-week double-blind
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`maintenance treatment phase. Per the Schedule of Event Table in the protocol, the randomization
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`and Maintenance Visit 1 (MV1) were planned to occur on Day 23, Maintenance Visit 2 (MV2)
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`on Day 51, Maintenance Visit 3 (MV3) on Day 79, and Maintenance Visit 4 (MV4) on Day 100,
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`with a window of ± 2 days. This indicates that the actual time length from randomization to MV4
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`was around 11 weeks and less than 12 weeks.
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`The primary efficacy endpoint was the change from pre-dose to 30 minutes post-dose in the
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`MDS-UPDRS Part III score at Week 12 (i.e. MV4).
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`The key secondary efficacy endpoint was the percentage of subjects with a patient-rated full “ON”
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`response within 30 minutes at Week 12.
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`3.2.2 Statistical Methodologies
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`The efficacy analysis population was the modified intent-to-treat (mITT) population, defined as
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`all subjects who were randomized, received at least one dose of study medication, and had at one
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`post-randomization evaluation.
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`The primary endpoint was analyzed using a mixed model with repeated measure (MMRM), with
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`treatment, visit (MV1, MV2, MV3, and MV4), treatment by visit interaction as fixed effects and
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`the change from pre-dose to 30 minutes post-dose in the MDR-UPDRS Part III score at the last
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`titration visit as the covariate. The unstructured variance-covariance matrix was used for the
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`The key secondary endpoint was analyzed using a generalized linear mixed model on binary data
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`with logit link. The model included treatment, visit (MV1, MV2, MV3, and MV4), and treatment
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`by visit interaction as fixed effects and the “ON/OFF” assessment at the last titration visit as the
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`covariate. The unstructured variance-covariance matrix was used for the analysis.
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`The primary and key secondary endpoints were planned to be tested sequentially, each test at the
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`two-sided significance level of 0.05.
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` 8
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`Reference ID: 4365433Reference ID: 4613103
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`

`

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` 3.2.3 Patient Disposition, Demographic and Baseline Characteristics
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` Table 2. Patient disposition (randomized population)
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` Source: Table 7 on page 63 of the clinical study report body
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` Table 2 presented the patient disposition of the randomized population. For Study CTH-300, the
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` randomized population is also the mITT population. A total of 219 subjects were screened in 32
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` study centers in the United States (US) and 1 center in Canada; a total of 109 subjects were
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` randomized in 27 centers in the US and 1 center in Canada. Among the 109 randomized patients,
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` 55 patients (50.5%) were randomized to the placebo group and 54 (49.5%) to the APL-130277
`
`
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`
`
`
`
`
`
` group.
`
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`
`
`
`
`
`
`
`
` A total of 80 patients completed the study: 46 in the placebo group and 34 in the APL-130277
`
`
`
`
` group. Compared to patients in the placebo group, more patients in the APL-130277 group
`
`
`
`
`
`
`
`
`
` discontinued due to adverse events: 15 patients in the APL-130277 group discontinued due to
`
`
`
`
`
`
`
`
` adverse events versus 4 patients in the placebo discontinued for the same reason.
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` 9
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`
`
`Reference ID: 4365433Reference ID: 4613103
`
`

`

` Table 3. Patient demographics (mITT population)
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`
` Source: selected from Table 10 on pages 66-67 of the clinical study report body
`
`Table 3 summarized the patient demographic characteristics of the mITT population. The
`
`
`
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`
`
`
`
`
`
`treatment groups appeared similar in terms of age, gender, and race. The average age of the
`
`
`
`
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`
`
`
`mITT population was approximately 62.7 years (standard deviation (SD) = 8.95). Overall, there
`
`
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`
`
`
`
`
`were more male patients than female patients in the study. The majority of the mITT population
`
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`
`
`was White.
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` 10
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`
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`Reference ID: 4365433Reference ID: 4613103
`
`

`

` Table 4. Patient baseline characteristics (mITT population)
`
`
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`
`
`
`
`
`
`
`
`
`
` Characteristic
`
`
` Placebo
`
`
` N = 55
`
`
` APL-130277
`
`
` N = 54
`
`
` All
` N = 109
`
`
`
`
`
`
`
`
` Time since diagnosis of PD (year)
`
`
`
`
`
`
` Mean (SD)
`
` Median
` Min, Max
`
`
`
`
`
`
` 9.3 (3.84)
`
` 8.0
`
` 2, 22
`
` Time since motor fluctuations started (year)
`
`
`
`
`
`
`
`
`
`
`
`
` Mean (SD)
`
` Median
` Min, Max
`
`
`
`
`
`
` 4.5 (3.78)
`
` 3.0
`
` 0.5, 22.0
`
` Number of “OFF” episodes typically experienced per day
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Mean (SD)
`
` Median
` Min, Max
`
`
`
`
`
`
` 3.8 (1.40)
`
` 4
`
` 1, 8
`
` Typical lengths of “OFF” episodes (minute)
`
`
`
`
`
`
`
`
`
`
`
`
` Mean (SD)
`
` Median
` Min, Max
`
`
`
`
`
`
` Total daily levodopa dose (mg)
`
`
`
`
` Mean (SD)
`
` Median
` Min, Max
`
`
`
`
`
`
` 66.1 (30.09)
`
` 60
`
` 30, 150
`
`
`
`
`
` 63.7 (31.91)
`
` 60
`
` 20, 210
`
`
`
`
`
` 64.9 (30.89)
`
` 60
`
` 20, 210
`
`
`
`
`
` 1007.7 (562.33) 1058.7 (563.30)
`
` 1000
`
` 900
`
` 400, 2940
`
` 400, 2900
`
`
`
`
`
`
` 1033.0 (560.78)
`
` 950
`
` 400, 2940
`
`
`
` 8.7 (4.25)
`
` 7.0
`
` 2, 20
`
`
`
` 4.7 (3.92)
`
` 4.0
`
` 0.5, 21.0
`
`
`
` 3.9 (1.17)
`
` 4
`
` 2, 8
`
`
`
`
` 9.0 (4.04)
`
` 8.0
`
` 2, 22
`
`
`
`
` 4.6 (3.83)
`
` 4.0
`
` 0.5, 22.0
`
`
`
`
` 3.9 (1.29)
`
` 4
`
` 1, 8
`
`
`
`
`
`
`
`
`
`
`
` mITT: modified intent-to-treat; N: number of patients; PD: Parkinson’s disease; SD: standard deviation.
`
`
`
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`
`
`
` Source: selected from Table 11 on pages 68-69 of the clinical study report body
`
`
`
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`
`
`
`
`
`
`
`
` Table 4 summarized the patient baseline characteristics of the mITT population. The placebo
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` group and APL-130277 group appeared similar. Patients in the mITT population were diagnosed
`
`
`
`
`
`
` with PD with an average diagnose length of 9.0 years (SD = 4.04) at study baseline. On average,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` patients had experienced motor fluctuations for approximately 4.6 years (SD = 3.83) at study
`
`
`
`
`
`
`
`
`
` baseline.
`
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`
`
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`
`
`
`
` 11
`
`
`
`Reference ID: 4365433Reference ID: 4613103
`
`

`

`
`
`
`
`
`
`
` 3.2.4 Results and Conclusions
`
`
`
`
`
`
`
`
`
` Figure 3. Observed mean (± standard error) change from pre-dose to 30 minutes post-
`
`
` dose in the MDS-UPDRS Part III score by visit and treatment (mITT
`
`
`
`
`
`
`
`
` population)
`
`
`
`
`
`
`
`
`
`
`
`
` Source: statistical reviewer
`
`
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`
`
`
`
`
`
`
`
` Figure 3 illustrated observed means of the change from pre-dose to 30 minutes post-dose in the
`
`
` MDS-UPDRS Part III score by visit and treatment for the mITT population. The APL-130277
`
`
`
`
`
`
`
`
` group appeared to have consistent mean improvements of the MDS-UPDRS Part III score based
`
`
`
`
`
`
`
`
`
`
`
`
` on the observed mean changes from pre-dose to post-dose assessments. Such improvements were
`
`
`
`
`
`
`
`
`
`
` on average greater than those from the placebo group at each maintenance visit. However, the
`
`
`
`
`
`
`
`
`
`
`
`
` placebo effect also appeared to exist. The observed mean changes of pre-dose to post-dose
`
`
`
`
`
`
`
`
`
`
`
`
` appeared to decrease over time for both treatment groups, but the trends could be affected by
`
`
`
`
`
`
`
`
`
`
`
` high percentages of missing observations in both treatment groups. The percentages of missing
`
`
`
`
`
`
`
` observations at MV4 were 16.4% and 37.0% for the placebo group and APL-130277 group,
`
`
`
`
`
`
`
`
`
`
` respectively.
`
`
`
`
`
`
` 12
`
`
`
`Reference ID: 4365433Reference ID: 4613103
`
`

`

`
` Table 5. Analysis of the change from pre-dose to 30 minutes post-dose in the MDS­
`
`
`
`
`
`
`
`
`
`
`
`
`
` UPDRS Part III score at Week 12 (mITT population)
`
`
`
`
`
`
`
`
`
` Source: Table 21 on page 85 of the clinical study report body
`
`
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`
`
`
` Table 5 presented the analysis results of the change from pre-dose to 30 minutes post-dose in the
`
`
`
`
`
` MDS-UPDRS Part III score at Week 12. APL-130277 was statistically significantly better than
`
`
`
`
`
`
`
` placebo (p-value = 0.0002), with a least square APL-130277-placebo difference of -7.6 points
`
`
`
`
`
`
`
`
`
` (95% Confidence Interval (CI) = (-11.5, -3.7)). The Applicant performed several sensitivity
`
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`
`
`
`
`
`
` analyses with missing data imputed under the missing at random assumption and the missing not
`
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`
`
`
`
`
`
`
`
` at random assumption, respectively. The results from these sensitivity analyses supported the
`
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`
`
`
`
`
`
`
`
`
`
` primary analysis results. For example, the Applicant used multiple imputation assuming that the
`
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`
`
`
`
`
`
`
`
`
` trajectories of the patients after discontinuation follow those of the placebo group and obtained a
`
`
`
`
`
`
`
` nominal p-value = 0.0068. Applicant’s tipping point analysis assumed that trajectories of the
`
`
`
`
`
`
`
`
` patients in the APL-130277 group after discontinuation are worse by delta and showed that the
`
`
`
`
`
`
`
`
`
`
`
` statistical significance was lost when delta was greater than 8 points in MDS-UPDRS Part III
`
`
`
`
`
`
`
`
`
`
`
`
`
` score.
`
`
`
`
`
`
` 13
`
`
`
`Reference ID: 4365433Reference ID: 4613103
`
`

`

`
`
`
`
`
`
` Figure 4. Least square mean (± standard error) change from pre-dose to 30 minutes
`
` post-dose in the MDS-UPDRS Part III score by visit and treatment (mITT
`
`
`
`
`
`
`
` population)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Source: Figure 14.2.1.1.2 of the clinical study report
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Figure 4 illustrated estimated means of the change from pre-dose to 30 minutes post-dose in the
`
`
` MDS-UPDRS Part III score by visit and treatment for the mITT population. The least square
`
`
`
`
`
`
`
`
` means were estimated from the primary analysis model. This figure confirmed the findings from
`
`
`
`
`
`
`
`
`
`
`
` Figure 3. Both the placebo effect and drug effect appeared to diminish over time while the APL­
`
`
`
`
`
`
`
`
`
`
` 130277-placebo difference appeared to be consistent over time. The difference between the
`
`
`
`
`
`
`
`
`
` observed mean and least square mean for the APL-130277 group is the largest at MV4,
`
`
`
`
`
` compared to the differences of observed mean and least square mean for the APL-130277 group
`
`
`
`
`
`
` at other maintenance visits. This is likely caused by the high percentage of missing observations
`
`
`
`
`
`
`
`
`
`
`
`
` at MV4.
`
`
`
`
`
`
`
` 14
`
`
`
`Reference ID: 4365433Reference ID: 4613103
`
`

`

`
`
`
`
`
`
`
` Table 6. Analysis of the percentage of subjects with a subject-rated full "ON" response
`
` within 30 minutes at Week 12 (mITT population)
`
`
`
`
`
`
`
`
`
`
`
`
` Source: Table 27 on page 95 of the clinical study report body
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 6 presented the analysis results of the percentage of subjects with a subject-rated full
` "ON" response within 30 minutes at Week 12. Disregarding the missing observations at MV4,
`
`
`
`
`
`
`
`
`
` the observed responder rates were 9/46 (19.57%) and 14/34 (41.18%) for the placebo group and
`
`
`
`
`
`
`
`
` APL-130277 group, respectively. APL-130277 was statistically significantly better than placebo
`
`
`
`
`
`
`
`
` (p-value = 0.0426) in terms of the percentage of subjects with a subject-rated full "ON" response
`
`
`
`
`
`
`
`
`
`
`
`within 30 minutes at Week 12, with an adjusted Odds Ratio of 2.81 (95% CI = (1.036, 7.644)).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` However, the Applicant’s pre-specified sensitivity analysis - Cochran-Mantel-Haenszel test - did
`
`
`
`
`
`
`
`
` not have a nominally significant p-value (nominal p-value = 0.174). Additional sensitivity
`
`
`
`
`
`
`
`
` analysis by the statistical reviewer imputing all missing data as non-responses did not have a
`
`
`
`
`
`
`
`
`
`
`
` nominally significant p-value either.
`
`
`
`
`3.3 Evaluation of Safety
`
`
`
`
`Please refer to Dr. Kenneth Bergmann’s clinical review for a detailed evaluation of safety.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
`
`
`
`
`4.1 Gender, Race, Age, and Geographic Region
`
` Overall, there is no compelling evidence from the subgroup analyses that a specific gender, race, or
`
`
`
`
`
`
`age subgroup benefits differently from APL-130277.
`
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`
`
`
`
` 15
`
`
`
`Reference ID: 4365433Reference ID: 4613103
`
`
`
`

`

`
`
` Gender
`
`
`
`
`
`
`
`
`
`
` Table 7. Subgroup analysis by gender of the change from pre-dose to 30 minutes post-
`
`
`
` dose in the MDS-UPDRS Part III score at Week 12 (mITT population)
`
`
`
`
`
`
`
`
`
`
`
`
`
` Gender
`
`
`
`
` Change from pre-dose to
`
` 30 minutes post-dose in the
`
`
` MDS-UPDRS Part III score
`
`
`
`
`
`
` Placebo
`
`
`
` APL-130277
`
`
`
` Baseline
`
`
`
` Female
`
`
`
` Male
`
`
`
`
`
` N
`
` Means (SD)a
`
` N
` Means (SD)a
`
`
`
`
`
`
`
`
` 24
`
` -26.6 (11.49)
`
` 31
`
` -24.9 (12.80)
`
`
`
`
`
`
` 17
`
` -27.2 (9.23)
`
` 37
`
` -19.2 (10.08)
`
`
`
`
`
`
`
` Week 12
`
`
`
` Female
`
`
`
` Male
`
`
`
`
`
`
`
`
`
`
` 10
` N
`
`
` 17
` Means (SD)a
`
` -7.5 (8.21)
`
` -6.9 (10.93)
`
` 24
`
` N
`
` 29
` Means (SD)a
`
`
`
` -11.0 (7.82)
`
`
` -2.1 (6.54)
`
`MDS-UPDRS: Movement Disorders Society -Unified Parkinson’s Disease Rating Scale; mITT: modified intent-to-treat; N:
`
`
`
`
`
`
`
`
`number of mITT patients; SD: standard deviation.
`
`
`
`
`
`a Obtained from all observations in the gender specific mITT population, without imputation.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Source: selected from Table 14.2.1.9.2 of the clinical study report
`
`
`
`
`
`
` As shown in Table 7, for both the female group and male group, the observed mean change from
`
` pre-dose to 30 minutes post-dose in MDS-UPDRS III score of the APL-130277 group was
`
`
`
`
`
`
`
`
` higher than that of the placebo group.
`
`
`
`
`
`Race
`
`
`
`
`
`
`
`
`
`
`
`
`
`As shown in Table 3, 92.7% of the mITT population was White. The numbers of patients in
`
`
`
`
`
`
`
`
`
`other races are so small that the analysis of other races would not be informative. Therefore,
`
`
`
`
`
`
`subgroup analyses by race were not performed.
`
`
`
`
`
`
`
`
`
` 16
`
`
`
`Reference ID: 4365433Reference ID: 4613103
`
`

`

`
` Age
`
`
`
`
`
`
`
`
`
`
`
`
` Table 8. Subgroup analysis by age group of the change from pre-dose to 30 minutes post-
`
`
` dose in the MDS-UPDRS Part III score at Week 12 (mITT population)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Change from pre-dose to
`
` 30 minutes post-dose in the
`
`
` MDS-UPDRS Part III score
`
`
`
`
`
`
` Placebo
`
`
`
` APL-130277
`
`
`
` Age Group
`
`
`
` Baseline
`
`
`
` < 65 years
`
`
`
`
`
` ≥ 65 years
`
`
`
`
`
` N
`
` Means (SD)a
`
` N
` Means (SD)a
`
`
`
`
`
`
`
`
` 34
`
` -26.4 (12.18)
`
` 21
`
` -24.4 (12.33)
`
`
`
`
`
`
` 30
`
` -23.7 (9.15)
`
` 24
`
` -19.3 (11.60)
`
`
`
`
`
` Week 12
`
`
`
`
`
`
`
`
`
`
`
`
`
` < 65 years
`
`
`
`
`
` ≥ 65 years
`
`
` 18
` N
`
`
` 28
` Means (SD)a
`
` -9.9 (9.23)
`
` -4.4 (9.21)
`
` 16
`
` N
`
` 18
` Means (SD)a
`
`
`
` -10.0 (6.59)
`
`
` -3.1 (7.83)
`
`MDS-UPDRS: Movement Disorders Society -Unified Parkinson’s Disease Rating Scale; mITT: modified intent-to-treat; N:
`
`
`
`
`
`
`
`
`number of mITT patients; SD: standard deviation.
`
`
`
`
`
`a Obtained from all observations in the age group specific mITT population, without imputation.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Source: selected from Table 14.2.1.8.2 of the clinical study report
`
`
`
`
`
`
`
`
`
` As shown in Table 8, for both the “< 65 years” group and “≥ 65 years” group, the observed
`
` mean change from pre-dose to 30 minutes post-dose in MDS-UPDRS III score of the APL­
`
`
`
`
`
`
`
`
`
`
`
`
`
` 130277 group was higher than that of the placebo group.
`
`
`
`
`
`Geographic Region
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Study CTH-300 was conducted mainly in the US. Only one patient the mITT population was
`
`
`
`
`
`
`
`
`
`
`
`from a Canadian study center. Therefore, subgroup analysis by geographic region (US vs. non-
`
`
`US) was not performed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 17
`
`
`
`Reference ID: 4365433Reference ID: 4613103
`
`

`

`
`
`
` 4.2 Other Special/Subgroup Populations
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 9. Subgroup analysis by randomized dose of the change from pre-dose to 30 minutes
` post-dose in the MDS-UPDRS Part III score at Week 12 (mITT population)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Randomized Doses
`
`
`
`
`
` Placebo
`
`
`
`
` Baseline
` Week 12
`
`
` n Mean (SD) n Mean (SD)
`
`
`
`
`
`
` -22.3 (12.25)
` -3.5 ( 7.42)
`
` 13
`
` 12
`
`
`
` APL-130277
`
`
`
`
` Baseline
` Week 12
`
`
` n Mean (SD) n Mean (SD)
`
`
`
`
`
`
` -25.6 (11.53)
`
` -9.5 (10.38)
`
`
` 7
`
` 4
`
`
`
` 11
`
`
`
` 16
`
` 9
`
`
`
` -27.9 (10.34)
`
`
`
`
`
` -24.94 (13.84)
`
`
`
` -29.1 (12.19)
`
`
`
` 8
`
`
`
` 15
`
` 7
`
`
`
`
`
` -18.8 ( 9.39)
`
`
`
`
`
` -13.4 ( 8.95)
`
`
`
`
`
`
`
` -9.5 ( 3.00)
`
`
`
` -6.9 ( 8.19)
`
` 12
`
` -23.8 (10.84)
`
`
`
` -10.0 ( 5.40)
`
`
`
`
`
`
`
`
`
` -3.6 ( 7.65)
`
`
`
` 18
`
`
`
` 7
`
`
`
` -4.3 (11.04)
`
`
`
`
`
`
`
` -20.6 ( 7.91)
`
`
`
`
`
` 12
`
`
`
` 4
`
`
`
` 8
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1.50 ( 3.87)
`
`
`
` 4
`
`
`
` 6
`
`
`
` -23.3 (11.59)
`
`
`
`
`
` -22.0 (14.75)
`
`
`
`
`
` -21.7 (10.44)