CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`215859Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`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
`
`STATISTICAL REVIEW AND EVALUATION
`Clinical Studies
`
`NDA #:
`Supplement #:
`Drug Name:
`Indication(s):
`
`Applicant:
`
`Receipt Date:
`PDUFA Date:
`Review Priority:
`
`215859
`0001
`Xarelto (Rivaroxaban)
`1) Venous thromboembolism (VTE) treatment and reduction of
`risk of VTE recurrence in pediatric patients (<18y)
`2) Thromboprophylaxis in pediatric patients (2y to 8y) with
`congenital heart disease after the Fontan procedure
`Janssen Pharmaceuticals Inc.
`
`Jun 22, 2021
`Dec 22, 2021
`Priority
`
`Biometrics Division:
`Division of Biometrics IX
`Statistical Reviewer:
`Huan Wang, PhD
`Concurring Reviewers: Yeh-Fong Chen, PhD (Team Leader)
`Thomas Gwise, PhD (Division Director)
`
`Medical Division:
`Clinical Team:
`
`Project Manager:
`
`Division of Nonmalignant Hematology
`Carrie Diamond, MD
`Ann Farrell, MD (Division Director)
`Carleveva Thompson, MS
`
`EDR Location:
`
`\\CDSESUB1\evsprod\NDA215859\0001
`
`Reference ID: 4899369
`
`

`

`Table of Contents
`1. EXECUTIVE SUMMARY ..................................................................................................................................5
`2. REGULATORY BACKGROUND .....................................................................................................................6
`3. DATA SOURCES AND SUBMISSION LINKS ................................................................................................6
`4.
`STATISTICAL EVALUATION .........................................................................................................................7
`4.1
`PHASE III 14372 (EINSTEIN JR) STUDY ........................................................................................................7
`4.1.1
`Study Design ...........................................................................................................................................7
`4.1.2
`Endpoints and Statistical Methodologies................................................................................................8
`4.1.3
`Patient Disposition................................................................................................................................10
`4.1.4
`Baseline Demographic Characteristics ................................................................................................11
`4.1.5
`Efficacy Results.....................................................................................................................................13
`4.1.6
`Safety Results ........................................................................................................................................16
`4.1.7
`Benefit-Risk Assessment........................................................................................................................18
`4.2
`PHASE III CHD3001 (UNIVERSE) STUDY...................................................................................................20
`4.2.1
`Study Design .........................................................................................................................................20
`4.2.2
`Endpoints and Statistical Methodologies..............................................................................................21
`4.2.3
`Patient Disposition................................................................................................................................22
`4.2.4
`Baseline Demographic Characteristics ................................................................................................23
`4.2.5
`Efficacy Results.....................................................................................................................................24
`4.2.6
`Safety Results ........................................................................................................................................26
`4.2.7
`Benefit-Risk Assessment........................................................................................................................27
`STATISTICAL ISSUES.....................................................................................................................................29
`5.
`6. CONCLUSIONS .................................................................................................................................................29
`7. LABELING RECOMMENDATIONS .............................................................................................................30
`8. REFERNCES ......................................................................................................................................................31
`
`Reference ID: 4899369
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`LIST OF TABLES
`Table 1: Treatment Disposition – FAS (EINSTEIN Jr Study) .....................................................................................10
`Table 2: Baseline Demographic Characteristics – FAS (EINSTEIN Jr Study)............................................................11
`Table 3: Results from the stratified Cox proportional hazard model: Primary efficacy outcome up to the end of main
`treatment period – FAS (EINSTEIN Jr Study).............................................................................................................13
`Table 4: Treatment group comparison for efficacy outcomes at the end of main treatment period – FAS (EINSTEIN
`Jr Study)........................................................................................................................................................................15
`Table 5: Results from the stratified Cox proportional hazard model: Treatment-Emergent Principal safety outcome
`up to the end of main treatment period – SAF (EINSTEIN Jr Study)..........................................................................16
`Table 6: Treatment group comparison for treatment-emergent safety outcomes at the end of main treatment period –
`SAF (EINSTEIN Jr Study) ...........................................................................................................................................17
`Table 7: Treatment Disposition – All Enrolled Subjects (UNIVERSE Study) ............................................................22
`Table 8: Baseline Demographic Characteristics – Full Analysis Set (UNIVERSE Study)..........................................23
`Table 9: Part B Treatment group comparison for efficacy outcomes at the end of main treatment period – Full
`Analysis Set (UNIVERSE Study).................................................................................................................................24
`Table 10: Part B Treatment group comparison for safety outcomes at the end of main treatment period – Safety
`Analysis Set (UNIVERSE Study).................................................................................................................................25
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`Reference ID: 4899369
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`LIST OF FIGURES
`Figure 1: Design overview (EINSTEIN Jr Study)..........................................................................................................7
`Figure 2: Kaplan-Meier cumulative incidence of the primary efficacy outcome during the main treatment period –
`FAS (EINSTEIN Jr Study) ...........................................................................................................................................14
`Figure 3: Kaplan-Meier cumulative incidence of the principal safety outcome during the main treatment period –
`SAF (EINSTEIN Jr Study) ...........................................................................................................................................16
`Figure 4: Forest plot for treatment group comparison of efficacy outcomes (FAS) and treatment-emergent safety
`outcomes (SAF) at the end of main treatment period (EINSTEIN Jr Study) ...............................................................18
`Figure 5: Design overview (UNIVERSE Study)..........................................................................................................19
`Figure 6: Forest plot for Part B treatment group comparison of efficacy outcomes (Full Analysis Set) and safety
`outcomes (Safety Analysis Set) at the end of main treatment period (UNIVERSE Study) .........................................27
`
`Reference ID: 4899369
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`1. EXECUTIVE SUMMARY
`Janssen Research & Development, LLC (JRD), on behalf of Janssen Pharmaceuticals, Inc.,
`submitted a new drug application (NDA) for Xarelto (rivaroxaban) oral suspension to support
`inclusion of the proposed new indications in the prescribing information. Xarelto was initially
`approved for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in
`patients undergoing hip or knee replacement surgery on July 1, 2011, and it was approved for the
`prophylaxis of venous thromboembolism (VTE) in adult patients on October 11, 2019. The
`current submission is for an oral suspension dosage form with two new indications for pediatric
`patients in responding to the FDA’s comments to the Sponsor’s exclusivity request: (1) for
`treatment of VTE and reduction in the risk of recurrent VTE in pediatric patients from birth to
`less than 18 years, and (2) for thromboprophylaxis in pediatric patients two years and older with
`congenital heart disease (CHD) after the Fontan procedure.
`
`This NDA includes two phase III clinical studies: Study 14372 (EINSTEIN Jr) and Study
`CHD3001 (UNIVERSE). EINSTEIN Jr was an open-label, active-controlled, randomized
`multicenter, multinational study in pediatric subjects (birth to <18 years) with acute VTE to
`evaluate the efficacy and safety of rivaroxaban compared to standard of care (SoC). A total of
`520 children were screened in 109 study centers in 28 countries and the study was conducted
`from November 13, 2014 to January 30, 2019. UNIVERSE was a prospective, open-label,
`active-controlled, multicenter, multinational study in pediatric subjects (2-8 years) with single-
`ventricle physiology who had completed the Fontan procedure within 4 months prior to
`enrollment to evaluate the PK and PK/PD profiles, safety and efficacy of rivaroxaban compared
`to Aspirin. A total of 112 subjects were enrolled in this study in 10 countries including the US
`and the study was conducted from November 17, 2016 to July 16, 2020.
`
`Although the two studies were not powered adequately for achieving statistical significance, the
`rivaroxaban has been shown with promising efficacy findings as a treatment for VTE and CHD
`thromboprophylaxis.
`
`In the EINSTEIN Jr study, the primary efficacy outcome (VTE recurrence) had a lower
`incidence rate in the rivaroxaban group (1.2%) than in the comparator group (3.0%) with a risk
`difference of -1.8% (95% CI: -6%, 0.64%) during the main treatment period. In the UNIVERSE
`study, the primary efficacy outcome (any thrombotic events) had a lower incidence rate in the
`rivaroxaban group (1.6%) than in the Aspirin group (8.8%) with a risk difference of -7.3% (95%
`CI: -22%, 1.1%). For safety outcomes, results of both studies were in general comparable
`between treatment groups. In the EINSTEIN Jr study, the principal safety outcome (composite of
`overt major and clinically relevant non-major bleeding) had an incidence rate of 3.0% in the
`rivaroxaban group and an incidence rate of 1.9% in the comparator group (risk difference =
`1.2%; 95% CI: -2.8%, 4.0%). In the UNIVERSE study, the primary safety outcome of major
`bleeding had an incidence rate of 1.6% in the rivaroxaban Part B group and 0% in the Aspirin
`group (risk difference = 1.6%; 95% CI: -9.9%, 8.4%).
`
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`Reference ID: 4899369
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`2. REGULATORY BACKGROUND
`This NDA (NDA 215859) serves as the Sponsor’s response to a Written Request (WR) for
`pediatric studies of rivaroxaban (Xarelto) for the purpose of pediatric exclusivity determination,
`and to fulfill the Pediatric Research Equity Act (PREA) Post-marketing Requirements (PMRs)
`under NDA 022406.
`
`On 30 August 2012, the VTE treatment and reduction in recurrence of VTE program, consisting
`of 6 studies (PMRs 1966-1, 1966-2, 1966-3, 1966-4, 1966-5, and 1966-6), was initially proposed
`as basis for requesting a WR.
`
`On 29 May 2015, at FDA’s request, the proposed pediatric study request was updated to include
`a thromboprophylaxis program in pediatric subjects with CHD post-Fontan procedure.
`
`On 04 August 2016, a Type C Meeting was held in which FDA agreed with the proposed use of
`granules for oral suspension formulation in the Phase 3 clinical studies in the VTE treatment and
`thromboprophylaxis program, and bridging strategy to support the introduction of the granules
`for oral suspension in the Phase 3 studies.
`
`On 08 June 2017, WR for Pediatric Studies was issued by FDA. The WR included all PREA
`PMR studies [PMR 1966-2 (WR study 1), 1966-3 (WR study 2), 1966-4 & 1966-5 (WR study
`4), and 1966-6 (WR study 3), UNIVERSE study (WR study 5) and excludes PMR 1966-1 (study
`report was submitted prior to obtaining the WR)].
`
`On 29 November 2017, a Type C Meeting was held in which FDA agreed on the alignment of
`pediatric clinical development studies between WR and PREA PMRs.
`
`On 23 March 2018, the WR Amendment 1 was issued by FDA to reflect the alignment of
`changes between WR and PREA PMR studies per agreement reached at the 29 November 2017
`Type C meeting.
`
`3. DATA SOURCES AND SUBMISSION LINKS
`Data were provided electronically in standard data format. The data submitted were considered
`acceptable by the FDA. SAS programs used to create key efficacy and safety outputs for the two
`studies were submitted along with the data.
`
`The links to the data of the two studies are listed below.
`
`EINSTEIN Jr
`UNIVERSE
`
`\\CDSESUB1\evsprod\NDA215859\0001\m5\datasets\14372
`\\CDSESUB1\evsprod\NDA215859\0001\m5\datasets\39039090chd3001
`
`On 3 August 2021, the FDA sent an Information Request (IR) regarding the interpretation of the
`benefit-risk forest plot for the EINSTEIN Jr study. The content of the IR and the response of the
`Sponsor can be found at: \\CDSESUB1\evsprod\NDA215859\0005\m1\us
`
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`On 23 November 2021, the FDA sent an IR to the Sponsor regarding the discrepancy in the
`calculation for the confidence intervals of the risk differences for the UNIVERSE study. The
`content of the IR and the response of the Sponsor can be found at:
`\\CDSESUB1\evsprod\NDA215859\0036\m1\us
`
`4. STATISTICAL EVALUATION
`4.1 Phase III 14372 (EINSTEIN Jr) Study
`
`4.1.1 Study Design
`EINSTEIN Jr Phase 3 was an open-label, active-controlled, randomized multicenter,
`multinational study in pediatric subjects (birth to <18 years) with acute VTE to evaluate the
`efficacy and safety of a body weight-adjusted rivaroxaban regimen administered either as tablets
`or granules for oral suspension, compared to SoC in pediatric subjects. The design overview is
`depicted in Figure 1 below. Enrollment was staggered by consecutive age cohorts: cohort 1 (12
`to <18 years), cohort 2 (6 to <12 years), cohort 3 (2 to <6 years), and cohort 4 (birth to <2 years).
`Eligible subjects with confirmed acute VTE were randomized (2:1) to receive either rivaroxaban
`(body weight-adjusted dose targeting the exposure range obtained in adults who received 20 mg
`once daily for the treatment of DVT) or SoC, i.e., unfractionated heparin (UFH), low-molecular-
`weight heparin (LMWH), fondaparinux with or without vitamin K antagonist (VKA).
`
`Figure 1: Design overview (EINSTEIN Jr Study)
`
`Note: CVC = central vein catheter; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; VTE =
`venous thromboembolism.
`Source: Section 7.1 of the CSR (PH-40166)
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`Subjects received either rivaroxaban or comparator for the main study treatment period of 3
`months (1 month for subjects with central venous catheter venous thromboembolism (CVC-
`VTE) aged <2 years). Diagnostic imaging was obtained at baseline and at the end of the main
`study treatment period if clinically feasible. After the completion of the main treatment period,
`study treatment could be continued for additional 3, 6, or 9 months (1 or 2 months for subjects
`<2 years with CVC-VTE) at the discretion of the investigator.
`
`Regardless of the duration of study treatment, an additional 30-day post-treatment observational
`safety follow-up period was to be completed for all children in the study. Subjects were required
`to be treated with UFH, LMWH, or fondaparinux for at least 5 days prior to start of study drug.
`Rivaroxaban was administered either as oral tablet or granules for oral suspension.
`
`4.1.2 Endpoints and Statistical Methodologies
`Analysis Sets:
` Full analysis set (FAS): This analysis set includes all randomized children.
` Safety analysis set (SAF): This analysis set includes all randomized children who
`received at least one dose of study medication.
` Per-protocol set (PPS): This analysis set excludes children with major protocol
`deviations.
` Listing-only set: This analysis set includes all screening failures.
`
`Efficacy Outcomes:
` Primary efficacy outcome: Composite of symptomatic recurrent VTE
` Secondary efficacy outcome: Composite of symptomatic recurrent VTE and asymptomatic
`deterioration in thrombotic burden on repeat imaging at the end of the main treatment period
` Further efficacy outcomes:
`o Composite of symptomatic recurrent VTE and major bleeding
`o Composite of symptomatic recurrent VTE and asymptomatic deterioration and no
`change in thrombotic burden assessment on repeat imaging at the end of the main
`treatment period
`o Composite of symptomatic recurrent VTE and thrombotic burden assessment at
`repeated imaging at the end of the main treatment period (symptomatic recurrent
`VTE, asymptomatic deterioration, no relevant change, uncertain, improved,
`normalized).
`o Normalization of thrombotic burden assessment on repeat imaging at the end of the
`main treatment period without confirmed symptomatic recurrent VTE
`o Fatal or non-fatal pulmonary embolism
`o Composite of symptomatic recurrent VTE and other clinically significant thrombosis
`Efficacy Analyses:
`All efficacy analyses were performed on the full analysis set population based on the outcomes
`confirmed by the central independent adjudication committee (CIAC).
`
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`The study was not designed to test a hypothesis regarding comparing incidences of outcomes
`between rivaroxaban versus comparator with standard of care. Incidence rates and cumulative
`incidences (time to first event; Kaplan-Meier [1]) were calculated for the efficacy outcomes by
`treatment group at 3 months for pooled data. In addition, incidence rates were calculated for each
`age stratum at 3 months and by baseline presentation of venous thrombosis. Incidence rates were
`calculated for the primary outcomes by treatment group and overall at 6, 9 and 12 months.
`Denominators were the number of patients at risk at the start of the respective period.
`
`Two-sided 95% confidence intervals for the frequency efficacy outcomes were calculated by
`applying the method of Blyth-Still-Casella [2, 3]. For time-to-event analyses, the censoring
`mechanism was assumed to be non-informative.
`
`Stratified (strata: cerebral vein and sinus thrombosis (CVST), CVC-VTE, non-CVC-VTE) Cox
`proportional hazards model was fitted for the primary efficacy outcome as exploratory analysis.
`Firth’s penalized maximum likelihood estimation was used to reduce bias in the parameter
`estimates. Point estimates for the hazard ratio, confidence interval (obtained with profile-
`likelihood function) and p-value for the treatment effect were obtained.
`Risk differences (differences in incidence rates) for the efficacy outcomes for the main treatment
`period were calculated between rivaroxaban and comparator overall with two-sided 95%
`confidence intervals by applying the method of Agresti-Min [4] as exploratory analysis.
`
`Safety Outcomes:
` Principal safety outcome: Composite of overt major and clinically relevant non-major
`bleeding.
` Further safety outcomes:
`o Death
`o Other vascular events (arterial thrombotic complications i.e., myocardial infarction,
`ischemic stroke, cerebrovascular accident, non-CNS systemic embolism)
`o Major bleeding
`o Clinically relevant non-major bleeding
`o Trivial bleeding
`Safety Analyses:
`For comparing incidences of outcomes between rivaroxaban versus comparator, stratified (strata:
`CVST, CVC-VTE+Unconfirmed/Unknown, non-CVC-VTE) Cox proportional hazards model
`was fitted for the time to principal safety outcome as an exploratory analysis. Firth’s penalized
`maximum likelihood estimation was used to reduce bias in the parameter estimates. Point
`estimates for the hazard ratio, confidence interval (obtained with profile-likelihood function) and
`p-value for the treatment effect were obtained.
`
`Risk differences (differences in incidence rates) for the safety outcomes for the main treatment
`period were calculated between rivaroxaban and comparator. Two-sided 95% confidence
`intervals were obtained by applying the method of Agresti-Min [4].
`
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`Sample Size Planning:
`There was no formal sample size calculation due to the low incidence of VTE in children, and
`the lack of well-documented information on recurrence rate and treatment effect with standard of
`care in children. There were at least 170 children to be enrolled in the study, with at least:
`20 children aged birth to 2 year, with at least 12 aged birth to <0.5 year,
`
`20 children aged 2 to <6 years,
`
`30 children aged 6 to <12 years, and
`
`80 children aged 12 to <18 years.
`
`
`Interim Analysis:
`No interim analysis was performed for this study.
`
`Multiplicity Adjustment:
`No multiplicity adjustment was applied because none of the analyses were intended for
`hypothesis testing.
`
`4.1.3 Patient Disposition
`A total of 520 children were screened in 109 study centers in 28 countries. 500 children
`passed the screening, were randomized (335 rivaroxaban, 165 comparator) and were valid for
`FAS. 491 children (329 rivaroxaban, 162 comparator) took at least one dose of study medication,
`and were valid for SAF.
`
`A total of 4871 children completed the main treatment period (Table 1), 218 (43.6%) entered and
`179 (82.1%) completed the first block of extended treatment, 91 (18.2%) entered and 84 (92.3%)
`completed the second block of extended treatment, and 48 (9.6%) entered and all (100%)
`completed the third block of extended treatment.
`
`1The number was manually corrected for database errors: 3 more children than given in the clinical database
`completed the main treatment period. For details see the corresponding CSR (PH-40166).
`
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`Table 1: Treatment Disposition – FAS (EINSTEIN Jr Study)
`
`
`
`Treatment Group
`
`
`
`Comparator
`Completed
`Took
`Reason for Non-
`n
`%
`Main
`Study
`Completion
`Treatment
`Medication
`Period
`Y
`
`Total
`
`%
`
`n
`
`484
`
`96.8
`
`96.36
`
`Rivaroxaban
`n
`%
`
`325
`
`97.01
`
`159
`
`N
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Y
`
`
`
`
`
`
`
`
`
`
` N
`
`
`
`Total
`Source: FDA analysis
`
`Death
`Efficacy outcome
`reached
`Lost to follow-up
`Physician
`decision
`Protocol violation
`Withdrawal
`by subject
`Total
`
`Withdrawal
`by subject
`Total
`
`1
`2
`0
`1
`1
`2
`7
`
`3
`3
`
`0.30
`0.60
`0.00
`0.30
`0.30
`0.60
`2.09
`
`0.90
`0.90
`
`0
`0
`1
`0
`0
`2
`3
`
`3
`3
`
`0.00
`0.00
`0.61
`0.00
`0.00
`1.21
`1.82
`
`1.82
`1.82
`
`1
`2
`1
`1
`1
`4
`10
`
`6
`6
`
`0.2
`0.4
`0.2
`0.2
`0.2
`0.8
`2.0
`
`1.2
`1.2
`
`335
`
`100.0
`
`165
`
`100.0
`
`500
`
`100.0
`
`A total of 469/500 (93.8%) children completed the 30-day post-study treatment follow up period.
`The main reasons for not completing the 30-day follow-up period were “withdrawal by subject”
`(5 rivaroxaban, 5 comparator) and “lost to follow-up” (4 rivaroxaban, 4 comparator).
`
`4.1.4 Baseline Demographic Characteristics
`Of the 500 randomized subjects, 49.0% were female, 79.0% were white, 5.0% were black, and
`5.6% were Asian. The mean age of subjects was 11.1 years (median 13.2 years), average weight
`was 46.4 kg (median 48.3 km), and average height was 141 cm (median 156 cm).
`
`Comparisons of patients’ baseline demographic characteristics data between the treatment groups
`overall and across the 5 age groups are shown in Table 2. In general, baseline demographic
`characteristics were balanced between the treatment groups.
`
`Reference ID: 4899369
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`Table 2: Baseline Demographic Characteristics – FAS (EINSTEIN Jr Study)
`< 6 months
`0.5 - <2 years
`2 - <6 years
`Rivaroxaban
`Comparator
`Rivaroxaban
`Comparator
`Rivaroxaban
`Comparator
`(N=16)
`(N=8)
`(N=21)
`(N=9)
`(N=47)
`(N=22)
`
`0.19 (± 0.16)
`
`0.08 (± 0.05)
`
`1.07 (± 0.48)
`
`1.31 (± 0.47)
`
`3.91 (± 1.18)
`
`4.12 (± 1.24)
`
`Age in Years
` Mean (SD)
`Sex
` F
`
`1 (12.5%)
`7 (87.5%)
`
`10 (47.6%)
`11 (52.4%)
`
`5 (55.6%)
`4 (44.4%)
`
`24 (51.1%)
`23 (48.9%)
`
`9 (40.9%)
`13 (59.1%)
`
`4 (50.0%)
`
`12 (57.1%)
`
`7 (77.8%)
`
`40 (85.1%)
`
`17 (77.3%)
`
`0 (0%)
`
`2 (25.0%)
`
`2 (9.5%)
`
`4 (19.0%)
`
`0 (0%)
`
`1 (11.1%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`1 (2.1%)
`
`2 (4.3%)
`
`0 (0%)
`
`0 (0%)
`
`2 (9.1%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`1 (2.1%)
`
`0 (0%)
`
`2 (25.0%)
`0 (0%)
`
`3 (14.3%)
`0 (0%)
`
`0 (0%)
`1 (11.1%)
`
`3 (6.4%)
`0 (0%)
`
`3 (13.6%)
`0 (0%)
`
`3.60 (± 0.85)
`
`9.40 (± 2.37)
`
`9.99 (± 2.69)
`
`15.88 (± 3.39)
`
`16.32 (± 3.24)
`
`51.29 (± 4.81)
`
`72.99 (± 7.99)
`
`77.41 (± 6.58)
`
`101.18 (±10.13)
`
`102.73 (± 9.41)
`
`13.41 (± 2.41)
`
`16.93 (± 2.62)
`
`16.42 (± 2.39)
`
`15.48 (± 1.97)
`
`15.36 (± 1.59)
`
`5 (31.3%)
`11 (68.8%)
`
`10 (62.5%)
`
`1 (6.3%)
`
`2 (12.5%)
`
`0 (0%)
`
`0 (0%)
`
`3 (18.8%)
`0 (0%)
`
`3.94 (± 0.92)
`
`53.81 (± 4.51)
`
` M
`Race
` WHITE
` BLACK OR
` AFRICAN
` AMERICAN
` ASIAN
` AMERICAN
` INDIAN OR
` ALASKA
` NATIVE
` NATIVE
` HAWAIIAN
` OR OTHER
` PACIFIC
` ISLANDER
` NOT
` REPORTED
` MULTIPLE
`Baseline
`Weight (kg)
` Mean (SD)
`Baseline
`Height (cm)
` Mean (SD)
`Baseline
`Body Mass
`Index
`(kg/m2)
`13.43 (± 1.46)
` Mean (SD)
`Source: FDA analysis
`
`Reference ID: 4899369
`
`12
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`

`Table 2: Baseline Demographic Characteristics – FAS (EINSTEIN Jr Study) (continued)
`6 - <12 years
`12 - <18 years
`Overall
`Rivaroxaban
`Comparator
`Rivaroxaban
`Comparator
`Rivaroxaban
`Comparator
`(N=67)
`(N=34)
`(N=184)
`(N=92)
`(N=335)
`(N=165)
`
`8.90 (± 1.75)
`
`9.04 (± 1.71)
`
`15.73 (± 1.48)
`
`15.74 (± 1.62)
`
`11.04 (± 5.84)
`
`11.27 (± 5.74)
`
`Age in Years
` Mean (SD)
`Sex
` F
`
`15 (44.1%)
`19 (55.9%)
`
`97 (52.7%)
`87 (47.3%)
`
`55 (59.8%)
`37 (40.2%)
`
`160 (47.8%)
`175 (52.2%)
`
`85 (51.5%)
`80 (48.5%)
`
`23 (67.6%)
`
`158 (85.9%)
`
`73 (79.3%)
`
`271 (80.9%)
`
`124 (75.2%)
`
`4 (11.8%)
`
`1 (2.9%)
`
`1 (2.9%)
`
`7 (3.8%)
`
`3 (1.6%)
`
`0 (0%)
`
`8 (8.7%)
`
`2 (2.2%)
`
`1 (1.1%)
`
`13 (3.9%)
`
`20 (6.0%)
`
`0 (0%)
`
`12 (7.3%)
`
`8 (4.8%)
`
`2 (1.2%)
`
`0 (0%)
`
`0 (0%)
`
`0 (0%)
`
`1 (0.3%)
`
`0 (0%)
`
`5 (14.7%)
`0 (0%)
`
`13 (7.1%)
`3 (1.6%)
`
`8 (8.7%)
`0 (0%)
`
`27 (8.1%)
`3 (0.9%)
`
`18 (10.9%)
`1 (0.6%)
`
`33.11 (± 11.40)
`
`68.38 (± 19.46)
`
`64.45 (± 18.59)
`
`46.70 (± 29.19)
`
`45.66 (± 26.87
`
`132.07 (±12.91)
`
`168.04 (±11.09)
`
`167.92 (± 9.62)
`
`140.71 (±37.43)
`
`141.37 (±36.16)
`
`18.35 (± 4.07)
`
`24.15 (± 6.51)
`
`22.57 (± 5.81)
`
`20.57 (± 6.58)
`
`19.96 (± 5.72)
`
`24 (35.8%)
`43 (64.2%)
`
`51 (76.1%)
`
`2 (3.0%)
`
`9 (13.4%)
`
`0 (0%)
`
`0 (0%)
`
`5 (7.5%)
`0 (0%)
`
`30.67 (± 10.91)
`
`133.17 (±12.55)
`
` M
`Race
` WHITE
` BLACK OR
` AFRICAN
` AMERICAN
` ASIAN
` AMERICAN
` INDIAN OR
` ALASKA
` NATIVE
` NATIVE
` HAWAIIAN
` OR OTHER
` PACIFIC
` ISLANDER
` NOT
` REPORTED
` MULTIPLE
`Baseline
`Weight (kg)
` Mean (SD)
`Baseline
`Height (cm)
` Mean (SD)
`Baseline
`Body Mass
`Index
`(kg/m2)
`16.97 (± 3.33)
` Mean (SD)
`Source: FDA analysis
`
`4.1.5 Efficacy Results
`Composite of symptomatic recurrent VTE (primary efficacy outcome) occurred in 4 of 335
`(1.2%; 95% CI: 0.4%, 3.0%) in the rivaroxaban group and 5 of 165 (3.0%; 95% CI: 1.2%, 6.6%)
`in the comparator group. The risk difference of the primary efficacy outcome between the
`rivaroxaban and comparator groups is -1.8% (95% CI: -6%, 0.64%).
`
`Reviewer’s comment: The primary method of CIs of all risk differences in Study EINSTEIN Jr
`is Agresti-Min method. FDA’s CIs were calculated by StatXact 11 and gamma = 0.000001,
`where gamma is the parameter for the restriction method proposed by Berger and Boos [5] to
`reduce the conservativeness caused by the unlikely values of the nuisance parameter. However,
`the Sponsor’s values were obtained by StatXact 10, although both results are very similar.
`
`13
`
`Reference ID: 4899369
`
`

`

`The hazard ratio of the primary efficacy outcome between the rivaroxaban and comparator
`groups is 0.40 (95% CI: 0.11, 1.41) with a p-value of 0.15 (Table 3).
`
`Table 3: Results from the stratified Cox proportional hazard model: Primary efficacy
`outcome up to the end of main treatment period – FAS (EINSTEIN Jr Study)
`Rivaroxaban
`Comparator
`Incidence Rate
`Incidence Rate
`
`Outcome
`
`p-value
`
`1.2%
`(4 / 335)
`
`3.0%
`(5 / 165)
`
`Composite of symptomatic
`recurrent VTE (Primary efficacy
`outcome)
`Notes: Estimates were based on stratified (strata: CVST, CVC-VTE, non-CVC-VTE) proportional hazard model.
`Notes: Firth’s penalized maximum likelihood estimation was used to obtain parameter estimates and profile-
`likelihood confidence intervals.
`Source: FDA analysis
`
`0.15
`
`Hazard Ratio between
`Rivaroxaban and Comparator
`(95% CI)
`0.40
`(0.11,1.41)
`
`In the clinical study report for PH-40166, the Sponsor conducted a sensitivity analysis to
`evaluate the potential influence of dropouts on the incidence of the primary efficacy outcome for
`the main treatment period. In this analysis subjects with premature termination before the end of
`intended main treatment period were assumed as having hazard of recurrence of VTE 1.5 times
`and twice as high as the hazard calculated including all patients within each treatment group
`assuming informative censoring. The results of the sensitivity analysis showed that even if one
`assumed that dropouts in the rivaroxaban group were more likely (1.5 and 2.0 times more likely
`applying the respective informative missingness hazard ratio) to have a primary efficacy
`outcome than those in the comparator group, the observed point estimates of the comparisons
`between rivaroxaban and comparator were similar.
`The Kaplan-Meier cumulative incidences of the primary efficacy outcome in the rivaroxaban and
`comparator groups during the main study treatment period on the full analysis are shown in
`Figure 2 below. The observed cumulative incidence rate was lower in the rivaroxaban group than
`in the comparator group.
`
`Reference ID: 4899369
`
`14
`
`

`

`Figure 2: Kaplan-Meier cumulative incidence of the primary efficacy outcome during the
`main treatment period – FAS (EINSTEIN Jr Study)
`
`Source: FDA analysis
`
`A summary of the incidence rates for efficacy outcomes in the rivaroxaban and comparator
`groups and risk differences between the two treatment groups is provided in Table 4 below.
`
`Reference ID: 4899369
`
`15
`
`

`

`Table 4: Treatment group comparison for efficacy outcomes at the end of main treatment
`period – FAS (EINSTEIN Jr Study)
`
`Rivaroxaban
`Incidence
`(95% CIa)
`Rate
`
`Comparator
`Incidence
`(95% CIa)
`Rate
`
`Risk Difference
`between
`Rivaroxaban
`and
`Comparator
`(95% CIb)
`−1.8%
`(−6%, 0.64%)
`−2.1%
`(−6.5%, 0.57%)
`
`(1.2%, 6.6%)
`
`(1.6%, 7.6%)
`
`(2.0%, 8.4%)
`
`(7.3%, 17.4%)
`
`−3%
`(−7.5%, −0.28%)
`−5.2%
`(−11%, −0.16%)
`
`1.2%
`(4 / 335)
`1.5%
`(5 / 335)
`
`1.2%
`(4 / 335)
`6.3%
`(21 / 335)
`
`(0.4%, 3.0%)
`
`(0.6%, 3.4%)
`
`(0.4%, 3.0%)
`
`(4.0%, 9.2%)
`
`3.0%
`(5 / 165)
`3.6%
`(6 / 165)
`
`4.2%
`(7 / 165)
`11.5%
`(19 / 165)
`
`Outcome
`
`Composite of symptomatic recurrent
`VTE (Primary efficacy outcome)
`Composite of Symptomatic recurrent
`VTE and asymptomatic deterioration in
`thrombotic burden on repeat imaging
`(Secondary efficacy outcome)
`Composite of symptomatic recurrent
`VTE and major bleeding
`Composite of symptomatic recurrent
`VTE and asymptomatic deterioration
`and no change in thrombotic burden
`assessment on repeat imaging at the end
`of the main treatment period
`Not normalization of thrombotic burden
`assessment on repeat imaging at the end
`of the main treatment period without
`confirmed symptomatic recurrent VTE
`Fatal or non-fatal pulmonary embolism
`
`61.8%
`(207 / 335)
`
`(56.5%, 67.0%)
`
`73.9%
`(122 / 165)
`
`(67.0%, 80.2%)
`
`−12%
`(−20%, −3.4%)
`
`0.3%
`(1 / 335)
`1.5%
`(5 / 335)
`
`(0.0%, 1.6%)
`
`(0.6%, 3.4%)
`
`0.6%
`(1 / 165)
`3.6%
`(6 / 165)
`
`(0.0%, 3.1%)
`
`(1.6%, 7.6%)
`
`−0.31%
`(−3.2%, 1.1%)
`−2.1%
`(−6.5%, 0.57%)
`
`Composite of symptomatic recurrent
`VTE and other clinically significant
`thrombosis
`aCIs for incidence rates were calculated by applying the Blyth-Still-Casella method.
`bCIs for risk differences were calculated by applying the Agresti-Min method.
`Note: Subjects were cou