Statistical Analysis Plan
Sponsor Name: Urovant Sciences GmbH
Protocol Number and Title: RVT-901-3003 An International Phase 3, Randomized, Double- Blind, Placebo- and Active (Tolterodine)- Controlled Multicenter Study to Evaluate the Safety and Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder
Protocol Version and Date: RVT-901-3003
Author(s): , , Biostats, Programming & Data Management, Urovant Sciences
SAP Version: 3.1
SAP Version Date: 06-MAR-2019
Notice of Confidential and Proprietary Information: The information contained in this document is confidential belonging to Urovant Sciences Acceptance of this document constitutes agreement by the recipient that no information contained herein will be published or disclosed without prior written authorization from an official of Urovant Sciences. However, this document may be disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized representatives of a national regulatory authority under the condition that they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, should be notified promptly.
Page 1 of 88 1 NCT Number: NCT03492281 This NCT number has been applied to the document for purposes of posting on clinicaltrials.gov Statistical Analysis Plan Urovant Protocol #3003
Version 3.1
Revision History
Version # Date Document Owner Revision Summary (dd-mmm-yyyy) 1.0 30APR2018 Initial Release Version
Additions to the efficacy section to include Multiple imputation instead of LOCF 2.0 20NOV2018 Minor changes to content to be in line with protocol version 2.1
Updates to shells per Sponsor comments; 3.0 05MAR2019 Addition of section on deviations from Protocol; Minor changes to content to be in line with Protocol version 3.0. Minor update to allow for the possibility to transform 3.1 06MAR2019 data prior to modeling for primary analyses if assumptions for the model are grossly violated.
Page 2 of 88 2 Statistical Analysis Plan Urovant Protocol #3003
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1 confirm that T have reviewed this document and agree with the content.
APPROVALS
Date (dd-Mmm-yyyy)
Date (dd-Mmm-yyyy)
Biostatistics
_ Sponsor Contact Date (dd-Mmm-yyyy)
, Biostats, Programming & Data Management
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3DJHRI Statistical Analysis Plan Urovant Protocol #3003
Version 3.1
LIST OF TABLES
Table 3.11.1: Schedule of Activities ...... 16 Table 6.5.1: Analysis Window ...... 37 Table 8.2.6.1 OAB-q LF Domain Questions ...... 54 Table 9.4.1: Laboratory Tests and Scheduled Study Visits ...... 67
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1. GLOSSARY OF ABBREVIATIONS
Abbreviation Description AE Adverse Event AIC Akaike’s Information Criteria ANCOVA Analysis of Covariance AR Autoregressive ATC Anatomical Therapeutic Chemical AUC Area Under the Curve BMI Body Mass index BP Blood Pressure BPH Benign Prostatic Hyperplasia BPM Beats Per Minute CI Confidence Interval CFB Change from Baseline CS Compound Symmetry ECDF Empirical Cumulative Distribution Function eCRF Electronic Case Report Form C24 24h Concentration CV Coefficient of Variation DBL Database Lock DBP Diastolic Blood Pressure DRM Data Review Meeting ECG Electrocardiogram EQ-5D EuroQual 5 Dimension Questionnaire FAS Full Analysis Set FAS-I Full Analysis Set for Incontinence GPP Good Pharmacoepidemiology Practice HRQL Health-Related Quality of Life ICF Informed Consent Form ICH International Conference on Harmonization IP Investigational Product IxRS Interactive Voice/Web Response System LOCF Last Observation Carried Forward LF Long Form MAR Missing at Random Max Maximum MedDRA Medical Dictionary for Regulatory Activities MI Multiple Imputation Min Minimum
Page 9 of 88 9 Statistical Analysis Plan Urovant Protocol #3003
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Abbreviation Description MMRM Mixed Model for Repeated Measures MNAR Missing Not At Random N/A Not Applicable NA Not Applicable NVU Night Time Voids Associated with Urgency OAB Overactive Bladder OAB Dry OAB in the absence of Incontinence OAB Type Investigator-Defined Baseline OAB Categorization OAB Wet OAB with Incontinence OAB-d Type eCRF Derived Baseline OAB Categorization OAB-q Overactive Bladder Questionnaire PGI Patient Global Impression PK Pharmacokinetic(s) PRO Patient Reported Outcomes PPS Per-Protocol Set PPS-I Per-Protocol Set for Incontinence PT Preferred Term PVR Post-Void Residual (Volume) QC Quality Control QTc Corrected QT Interval REML Restricted (or Residual) Maximum Likelihood RVT-901 Vibegron (Urovant Code Number) SAE Serious Adverse Event SAF Safety Set SAP Statistical Analysis Plan SBP Systolic Blood Pressure SD Standard Deviation SE Standard Error SOC System Organ Class SOP Standard Operating Procedure SUI Stress Urinary Incontinence TEAE Treatment Emergent Adverse Event TLF Table, Listing and Figure Urovant Urovant Sciences GmbH US United States UUI Urge Urinary Incontinence WHO World Health Organization WPAI-US Work Productivity and Activity Impairment Questionnaire-Urinary Symptoms
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Table Footnotes: Screening 1. The time between the Screening and Run-in Visits may be up to 5 weeks, to allow for washout of prior OAB medications (if needed) and completion of the Patient Voiding Diary and Urine Volume Diary. Electronic Diary (eDiary) 2. The Electronic Diary (eDiary) for this study includes both the Patient Voiding Diary and the Urine Volume Diary, and will be implemented via an eDiary device (provisioned smartphone). A paper diary will be provided to all patients to be used as a back-up when necessary. If a back-up paper diary is used, it should be collected at each study visit. eDiary Device 3. At Screening, site personnel will setup the eDiary Device, confirm proper functioning, and dispense the eDiary Device to the patient. At each subsequent visit during the Treatment Period, site personnel will confirm that the eDiary Device is functioning properly. 4. Specific training on device operation will be provided to the patient at Screening, with re-training provided at each subsequent visit.
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Patient Voiding Diary and Urine Volume Diary 5. Specific training on completion of the Patient Voiding Diary and Urine Volume Diary will be provided to the patient at Screening, with re-training provided at each subsequent visit. 6. The Patient Voiding Diary should be completed by the patient on all of the 7 Diary Days prior to the Run-in Visit (days -21 to - 15), Baseline Visit (days -7 to -1), Week 2 Visit (days 8 to 14), Week 4 Visit (days 22 to 28), Week 8 Visit (days 50 to 56), and Week 12 Visit (days 78 to 84). Patient will receive SMS text alerts and/or phone call reminders to complete the Diary. 7. The Urine Volume collection and Urine Volume Diary completion should be performed by the patient on one (1) of the 7 Diary Days prior to the Run-in, Baseline, and Weeks 2, 4, 8, and 12 Visits. Diary and Visit Reminders 8. Patient will receive phone call reminders from the site to complete the Diary on approximately the first day and third day of each diary collection period (or next business day). Patient may consent to additional SMS Text reminders (where available). Patient Reported Outcomes 9. Vital signs, followed by PRO Questionnaires will be the first procedure performed at visits that include PRO administration. Questionnaires will be administered at the site in the order listed in the Schedule of Activities. Post Void Residual Volume 10. All efforts will be made to ensure the same device and operator are used for all PVR volume measurements for individual patients. Physical/ECG/Vitals 11. A Complete Physical Exam will be performed at the Screening Visit and will include a digital rectal exam for all males. Focused physical examinations will be performed at the Run-in and Follow-up Visits, which will include a pelvic exam for women only as needed to confirm prolapse. 12. A single 12-lead ECG will be obtained at Screening. 13. Vital Signs includes Blood Pressure (average of three measurements taken 1-2 minutes apart after sitting for 5 minutes), Heart Rate, Temperature, Respiration Rate and Weight. Height will be measured only at Screening. Adverse Events 14. Adverse events will be collected from the time a patient provides informed consent to participate in the study until the Follow- up Visit is completed.
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15. Serious adverse events will be collected from the time a patient provides informed consent to participate in the study until the Follow-up Visit is completed. Prior and Concomitant Medications 16. Concomitant medications will be reviewed and recorded at each study visit from the Screening through the Week 12 and at any Unscheduled Visits. Medications taken within 1 year of the Screening Visit for the treatment of OAB will also be recorded. Labs 17. At Week 8, the Urine Dipstick will only be performed if clinically indicated (e.g., symptoms of urinary retention or urinary tract infection). 18. Urinalysis will be performed only if the urine dipstick tests positive for the presence of leukocytes, nitrites, or blood cells, and will be performed by the central lab. 19. Urine beta-human chorionic gonadotropin (β-hCG) will be tested for women of childbearing potential only. Dosing/Drug 20. Dosing will occur every day from the Witnessed Dose on the day of the Run-in Visit through the day before the Week 12 Visit. 21. Study Treatment bottles should be returned by the patient at each visit. Clinic staff will perform accountability and review any discrepancies with the patient during the visit. 22. All patients will take their dose of Study Treatment on the day of the Run-in and Baseline Visits at the site as a witnessed dose. The date and time of Study Treatment dosing will be recorded Pharmacokinetics Subset Only 23. PK samples for Population PK Analysis will be collected from a subset of patients (approximately 30% of enrolled patients) at selected sites. Pre-dose blood samples will be collected at Week 4, Week 8, and Week 12. PK samples should be collected during the clinic visit after all other study assessments have been completed. 24. The date and time of the last dose of Study Treatment prior to PK sampling will be recorded. Follow-up/Unscheduled 25. Unscheduled Visits and the specific procedures performed at these visits will be determined by the Investigator, as clinically indicated. The procedures indicated in the Schedule of Activities will be performed at these visits, as clinically indicated, based on the purpose of the visit (e.g., follow-up for an adverse event or abnormal laboratory test, study treatment dispensation). The reason for the visit will be captured in the source documents.
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26. For Patients who do not enroll into the optional extension study (RVT-901-3004) or patients who withdraw from the study for any reason, a Follow-up Visit should be performed approximately 28 days after the last dose of Study Treatment on Study Day 113 or approximately 28 days after a patient’s Withdrawal from the study. When a patient withdraws from the study prior to study completion, all applicable activities scheduled for the Week 12 Visit should be performed at the time of withdrawal.
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Other Major protocol deviation categories may include, but are not limited to the following: Informed Consent Issues IP Dispensation/Storage Lab Sample Issues (Missing/Not Analyzed etc.) AECI Not Reported
All major protocol deviations related to efficacy will be discussed during the BDRM, and decisions relating to exclusion for the PPS(-I) will be documented in the BDRM Report, finalized prior to unblinding.
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Statistical Analysis Plan Urovant Protocol #3003 Version 3.1
A nighttime void is defined as “Urinated in Toilet” as indicated on the voiding diary, after going to bed but prior to getting up the next day.
Nighttime UUI A nighttime UUI episode is defined as having "urge" as the main reason for the leakage as indicated on the voiding diary, regardless of whether more than one reason for leakage is checked, and occurring after going to bed, but prior to getting up the next day.
OAB Categorization There will be two different definitions of OAB Categorization used for the study: OAB Type and OAB-d Type. OAB Type will be based on the randomization strata and OAB-d Type will be derived based on the baseline diary data, defined below. Details on the derivation of baseline patient voiding diary endpoints are presented further below in this section (Definition of Baseline for Patient Voiding Diary Endpoints).
OAB-d Type (Wet, Dry, Missing) will be categorized based on Baseline diary data, as follows:
OAB Wet: Patients are considered OAB Wet according to the following criteria: An average of ≥ 8.0 micturitions per Diary Day; and, An average of ≥ 1.0 UUI episodes per Diary Day; and, If stress urinary incontinence (SUI) is present, the total number of UUI episodes must be greater than the total number of SUI episodes.
OAB Dry: Patients are considered OAB Dry according to the following criteria: An average of ≥ 8.0 micturitions per Diary Day; and, An average of ≥ 3.0 urgency episodes per Diary Day; and, An average of < 1.0 UUI episodes per Diary Day
OAB-d Type Missing: Patients are considered non-categorized for OAB if neither of the above criteria is achieved.
Where OAB Wet is discussed in this document, it pertains to patients randomized under the strata of OAB Wet; where all OAB Patients are discussed, this relates to all patients randomized as either OAB Wet or OAB Dry. Under the randomization strata, all patients are categorized as OAB Wet or Dry; missing is not present. Unless otherwise stated, for the purposes of the analyses, OAB Type (i.e. as randomized) will be used.
Diary Day
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32 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1
A “Diary Day” is defined as the time between when the patient gets up for the day each morning and the time the patient gets up for the day the next morning as recorded in the patient voiding diary.
Complete Diary Day A “Complete Diary Day” is defined as a Diary Day that includes input of micturition data by patients on the voiding diary. Unless a patient indicated “No” to the questions of “Did you record each time you urinated or leaked during this Diary Day” the Diary Day is considered complete.
For post-baseline diaries at Weeks 4 and 8, only complete diary days within 10 days prior to the study visit will be included. For the Week 12/Early Termination diary, only complete diary days within 14 days prior to the study visit will be included. For the Week 2 diary, complete diary days within 10 days prior to the target Week 2 day will be used. For diaries at all visits, if a patient has fewer than 4 complete diary days, that will be identified as a significant protocol deviation and that diary data will be excluded from all analysis.
Definition of Baseline for Patient Voiding Diary Endpoints Baseline will be the data collected during the Run-in Period. If greater than 10 complete diary days are available in the Run-in diary, only the complete diary days within the 10 days prior to the Baseline visit will be used; if 4 or more and less than 10 complete diary days are available, all complete diary days in the Run-in diary will be used to calculate Baseline. If less than 4 complete diary days are available, the Baseline will be regarded as missing. For a patient to have an evaluable change from baseline, the patient must have both a baseline diary and a post-baseline diary from any post-baseline timepoint, after analysis window has been applied (i.e., Week 2, Week 4, Week 8, or Week 12).
Definition of Baseline for Endpoints not Derived from the Patient Voiding Diary Baseline value for all secondary efficacy, exploratory and safety endpoints will be defined as the last non-missing assessment before starting double-blind treatment.
Screening/Washout Period The Screening/Washout Period covers Day -49 (Screening Visit) to Day -15 (the day before the start of the Run-in Period), which includes a 28-day washout period followed by 7-days of Diary completion. Patients not requiring the 28-day washout period can begin the 7-day Diary the day after the Screening Visit.
Run-in Period The Run-in Period covers the duration between screening (Day -14) and the day before baseline (Day 1). There is no day 0 included in the study.
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Statistical Analysis Plan Urovant Protocol #3003 Version 3.1
Incomplete/missing start and stop dates will be handled as follows:
Incomplete AE/Concomitant Medication Start Date
If only the start day is missing, then the start day will be imputed as the first day of the month that the event occurred with the following exceptions: (1) if the partial date is the same month and year as the date of first dose of run-in single-blind medication (or double- blind medication), then the partial date will be imputed as the date of first dose of single- blind medication (or double-blind medication). However, if the date of first dose of single- blind medication and date of first dose of double-blind medication occur in the same month, then the date of first dose of double-blind medication will be imputed. (2) if the partial date is before the date of first dose of run-in single-blind medication, then the start date will be sent as the date of informed consent.
If the start date is missing both the day and month, then the day and month will be imputed as the first day of the year (i.e., 01-Jan) with the following exceptions: if the partial date is in the same year as the first dose dose of run-in single-blind medication (or double-blind medication), then the partial date will be imputed as the date of first dose of single-blind medication (or double-blind medication). However, if the date of first dose of single-blind medication and date of first dose of double-blind medication occur in the same month, then the date of first dose of double-blind medication will be imputed. (2) if the start year is before the year of first dose of run-in single-blind medication, then the start date will be sent as the date of informed consent.
Incomplete AE/Concomitant Medication or Treatment End Date
If only the end day is missing, then the end day will be imputed as the last day (28/29/30/31) of the month of occurance. If the patient died in the same month, then set the imputed date as the death date.
If the day and month are missing, then the end day will be imputed as the 31st of December of year occurance. If the patient died in the same year, then set the imputed date as the death date.
Missing Wake/Bed Time
For a patient with a complete diary day, if the wake and/or bed time is missing for that day then the missing time will be imputed as the average of the other wake and/or bed times from that diary. E.g., for the Week 12 diary, if the patient has 4 complete diary days with 4 wake times, but only 3 bed times of 10:00pm, 10:10pm, and 10:20pm, then the missing bed time will be imputed as the average of the observed data which is 10:10pm.
Other Data
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Statistical Analysis Plan Urovant Protocol #3003 Version 3.1
Prior beta-3 agonist use in the last 12 months (yes vs. no) OAB Type (OAB Wet vs. OAB Dry) OAB-d Type (OAB Wet vs. OAB Dry)
The details of the analysis of subgroups used for statistical inference of the co-primary endpoints are given in Section 8.1.4. A list of anticholinergics is given in the protocol in Table 4 of Section 7.9.3.
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'RXEOH%OLQG3HULRG&RQFRPLWDQWPHGLFDWLRQVZLOOEHGHILQHGDVWDNHQGXULQJWKH5XQLQ 3HULRGLIPHGLFDWLRQVZHUHVWDUWHGRQRUDIWHUWKHILUVWGRVHRIVLQJOHEOLQGPHGLFDWLRQEXW SULRUWRWKHILUVWGRVHRIWKHGRXEOHEOLQGPHGLFDWLRQRUVWDUWHGSULRUWRWKHILUVWGRVHRIWKH VLQJOHEOLQG PHGLFDWLRQ DQG ZHUH FRQWLQXLQJ WR EH WDNHQ GXULQJ WKH 5XQLQ 3HULRG &RQFRPLWDQW PHGLFDWLRQV ZLOO EH GHILQHG DV WDNHQ GXULQJ WKH GRXEOHEOLQG SHULRG LI PHGLFDWLRQVZHUHVWDUWHGRQRUDIWHUWKHILUVWGRVHRIGRXEOHEOLQGPHGLFDWLRQEXWSULRUWR WKHODVW GRVHRIWKHGRXEOHEOLQGPHGLFDWLRQRUVWDUWHGSULRUWR GRXEOHEOLQGPHGLFDWLRQ DQGZHUHRQJRLQJGXULQJWKH'RXEOH%OLQG3HULRG3DUWLDOPHGLFDWLRQVWDUWGDWHVZLOOEH LPSXWHGDVGHWDLOHGLQ6HFWLRQ 2WKHU7KHUDSLHV 3ULRU2$%PHGLFDWLRQZLOOEHUHFRUGHGDWVFUHHQLQJYLVLW7KHIROORZLQJFULWHULRQZLOOEH XVHGIRUVHOHFWLQJSULRU2$%PHGLFDWLRQ 3DJHRI Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Table 7.5.3: OAB Medication Selection Class Variable Selected Selection Anticholinergics Preferred Term darifenacin, fesoterodine, festoterodine fumarate hyoscyamine, oxybutynin, oxybutynin hydrochloride, propantheline, solifenacin, solifenacin succinate, tolterodine, tolterodine l-tartrate, trospium, and trospium chloride Beta-3 adrenergic Preferred Term Mirabegron, vibegron agonists Page 42 of 88 42 6WDWLVWLFDO$QDO\VLV3ODQ 8URYDQW3URWRFRO 9HUVLRQ ()),&$&<$1$/<6,6 7KURXJKRXWWKHWULDOSDWLHQWVZHUHUHTXLUHGWRILOORXWDQHYHQWDQGYROXPHGLDU\,WZDV LQWHQGHG IRU WKH SDWLHQWV WR ILOO RXW WKH YRLGLQJ GLDU\ IRU GD\V SULRU WR WKH 5XQLQ %DVHOLQH:HHN:HHN:HHNDQG:HHNYLVLWVDQGWRILOORXWWKHYROXPHSRUWLRQ RIWKHGLDU\IRURIWKHGLDU\GD\VIRUHDFKYLVLW'XSOLFDWHGDWDUHFRUGHGE\WKHSDWLHQW LQGLDU\URZVZLWKLGHQWLFDOYDOXHVZLOOEHQRWUHPRYHG 7KH GHILQLWLRQV RI D ³'LDU\ 'D\´ ³&RPSOHWH 'LDU\ 'D\´ DQG %DVHOLQH DUH JLYHQ LQ 6HFWLRQ ,QRUGHUIRUDSDWLHQWWRKDYHDQHYDOXDEOHFKDQJHIURPEDVHOLQHWKHSDWLHQWPXVWKDYHERWK D FRPSOHWH EDVHOLQH GLDU\ DQG D SRVWEDVHOLQH DVVHVVPHQW IURP DQ\ SRVWEDVHOLQH YDOXH LH:HHN:HHN:HHNRU:HHN IRUHLWKHUPLFWXULWLRQVIRUWKH)$6RU88,IRU WKH )$6, &KDQJH IURP EDVHOLQH LV 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:HHNDQG:HHNDQGFRUUHFWVIRUGDWDWKDWLVPLVVLQJDWUDQGRP 0$5 DFFRXQWLQJ IRUWKHIDFWWKDWPHDVXUHPHQWVWDNHQRQWKHVDPHSDWLHQWRYHUWLPHWHQGWREHFRUUHODWHGE\ XVLQJ DOO DYDLODEOH LQIRUPDWLRQ RQ SDWLHQWV ZLWKLQ WKH VDPH FRYDULDWH VHW WR GHULYH DQ 3DJHRI Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 estimate of the treatment effect for a MAR-free population. No imputation of missing data is required for this analysis. The analysis model will include terms for treatment, visit, OAB Type (Wet vs Dry), Sex (Female vs Male), Region (US vs non-US), baseline score, and interaction of visit by treatment. Primary inference will be drawn from the treatment difference between vibegron and placebo at Week 12. The comparisons between tolterodine and placebo will be reported with nominal p-values. The standard error and 95% CI for the differences will also be presented with the corresponding p-values. Additionally, estimates of least-squares means, standard errors, and 95% CIs will be presented for each treatment group (placebo, vibegron and tolterodine). The table output will also include treatment group estimates and treatment differences between vibegron and placebo, and tolterodine and placebo at Weeks 2, 4, and 8 from this model. An unstructured covariance matrix will be used to model the correlation among repeated measurements. The Kenward-Roger adjustment will be used with restricted (or residual) maximum likelihood (REML) to make statistical inference. If the unstructured covariance model fails to converge with the default Newton-Raphson algorithm, the Fisher scoring algorithm will be used to provide initial values of the covariance parameters. In the rare event that none of the above methods yield convergence, the following structures will be investigated: heterogeneous Toeplitz, Toeplitz, heterogeneous First-Order Autoregressive [AR (1)], heterogeneous compound symmetry (HCS), and compound symmetry (CS). The covariance structure converging to the best fit, as determined by Akaike’s information criterion (AIC), will be used. An example of the SAS code for the base procedure is given below: proc mixed data = datain method = reml ; class TRTP AVISITN USUBJID OABTYPE SEX REGION ; model CHG = TRTP AVISITN OABTYPE SEX REGION BASE TRTP*AVISITN / ddfm=KR solution chisq ; REPEATED AVISITN / subject=USUBJID type=UN r rcorr ; LSMEANS TRTP*AVISITN / pdiff=all cl alpha=0.05 ; run ; Where TRTP is the planned treatment, AVISITN is the visit number, USUBJID is the unique patient identifier, OABTYPE indicates if the patient is Dry or Wet, SEX is female or male, REGION indicates if the patient is in the United States or in the non-US countries and BASE indicates baseline value. Model assumptions will be assessed through inspection of residual plots and normal probability plots. Should gross violations of the assumptions occur, the change from baseline in average daily micturitions will be transformed prior to the modeling. Page 44 of 88 44 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 8.1.1.2. Sensitivity Analysis Page 45 of 88 45 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Page 46 of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x 5HJLRQ 86YV1RQ86 R 7KH DQDO\VLV PRGHO IRU &)% LQ PLFWXULWLRQV ZLOO LQFOXGH WHUPV IRU WUHDWPHQWYLVLW2$%7\SH :HWYV'U\ 6H[ )HPDOHYV0DOH EDVHOLQH VFRUHUHJLRQLQWHUDFWLRQRIUHJLRQE\WUHDWPHQWDQGLQWHUDFWLRQRIYLVLWE\ WUHDWPHQW R 7KHDQDO\VLVPRGHOIRU&)%LQ88,HQGSRLQWZLOOH[FOXGHWKHWHUPRI2$% 7\SH x $JHFDWHJRU\ WR WR WR \HDUV R 7KLVFDWHJRU\ZLOORQO\EHXVHGIRUGHVFULSWLYHVWDWLVWLFV x $JHFDWHJRU\ \HDUV R 7KH DQDO\VLV PRGHO IRU &)% LQ PLFWXULWLRQV ZLOO LQFOXGH WHUPV IRU WUHDWPHQW YLVLW 2$%7\SH :HW YV'U\ 6H[ )HPDOHYV 0DOH 5HJLRQ 86YV1RQ86 EDVHOLQHVFRUHDJHFDWHJRU\LQWHUDFWLRQRIDJHFDWHJRU\ WUHDWPHQWDQGLQWHUDFWLRQRIYLVLWE\WUHDWPHQW R 7KHDQDO\VLVPRGHOIRU&)%LQ88,HQGSRLQWZLOOH[FOXGHWKHWHUPRI2$% 7\SH x $JHFDWHJRU\ WR WR \HDUV\HDUV R 7KLVFDWHJRU\ZLOORQO\EHXVHGIRUGHVFULSWLYHVWDWLVWLFV x 5DFH ZKLWHYVRWKHU R 7KH DQDO\VLV PRGHO IRU &)% LQ PLFWXULWLRQV ZLOO LQFOXGH WHUPV IRU WUHDWPHQW YLVLW 2$%7\SH :HW YV'U\ 6H[ )HPDOHYV 0DOH 5HJLRQ 86YV1RQ86 EDVHOLQHVFRUHUDFHLQWHUDFWLRQRIUDFHE\WUHDWPHQWDQG LQWHUDFWLRQRIYLVLWE\WUHDWPHQW R 7KHDQDO\VLVPRGHOIRU&)%LQ88,HQGSRLQWZLOOH[FOXGHWKHWHUPRI2$% 7\SH x 6H[ IHPDOHYVPDOH 3DJHRI Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 o The analysis model for CFB in micturitions will include terms for treatment, visit, OAB Type (Wet vs Dry), Region (US vs Non-US), baseline score, sex, interaction of sex by treatment, and interaction of visit by treatment. o The analysis model for CFB in UUI endpoint will exclude the term of OAB Type. Males with BPH vs. Males without BPH o This category will only be used for descriptive statistics. Prior Anticholinergic Use in the Last 12 Months (Yes vs No) o This category will only be used for descriptive statistics. Prior Beta-3 Agonist Use within the Last 12 Months (Yes vs No), o This category will only be used for descriptive statistics. OAB Type (OAB Wet vs. OAB Dry) o The analysis model for CFB in micturition will include terms for treatment, visit, OAB Type (Wet vs Dry), Sex (Female vs Male), Region (US vs Non- US), baseline score, interaction of OAB Type by treatment, and interaction of visit by treatment. o The analysis model for CFB in UUI endpoint will not be applicable for this subgroup analysis. OAB-d Type (OAB Wet vs. OAB Dry) o The analysis model for CFB in micturition will include terms for treatment, visit, OAB-d Type (Wet vs Dry), Sex (Female vs Male), Region (US vs Non-US), baseline score, interaction of OAB-d Type by treatment, and interaction of visit by treatment. o The analysis model for CFB in UUI endpoint will not be applicable for this subgroup analysis. A forest plot will be provided to present the results from subgroup analyses. Side-by-side 95% confidence intervals will be plotted for each comparison to control within each subgroup, where the 95% confidence intervals are taken from the analysis table described above. The confidence intervals are stacked vertically on the page, with a reference line at zero for mean. All the subgroups should be plotted on a single figure (using multiple pages, if necessary). Page 49 of 88 49 6WDWLVWLFDO$QDO\VLV3ODQ 8URYDQW3URWRFRO 9HUVLRQ .H\6HFRQGDU\(IILFDF\$QDO\VHV 0XOWLSOLFLW\DQG7HVWLQJ3URFHGXUHRI.H\6HFRQGDU\(QGSRLQWV ,IVWDWLVWLFDOVLJQLILFDQFHLVIRXQGDWWKHOHYHOIRUERWKFRSULPDU\HQGSRLQWVHDFKNH\ VHFRQGDU\ HQGSRLQW ZLOO EH WHVWHG VHTXHQWLDOO\ LQ WKH RUGHU JLYHQ LQ 6HFWLRQ ,I VWDWLVWLFDOVLJQLILFDQFHDWWKHOHYHOLVDFKLHYHGDWDOOSUHYLRXVNH\VHFRQGDU\HQGSRLQWV WKHQH[WVHTXHQWLDONH\VHFRQGDU\HQGSRLQWZLOOEHWHVWHG2QFHDNH\VHFRQGDU\HQGSRLQW LVIRXQGWREHLQVLJQLILFDQW LHSYDOXH WKHWHVWLQJSURFHGXUHZLOOVWRS)RUDOO VXEVHTXHQWNH\VHFRQGDU\HQGSRLQWVQRPLQDOSYDOXHVZLOOEHSURYLGHG 2QO\WKHHQGSRLQWVOLVWHGLQ6HFWLRQDQG6HFWLRQDUHSDUWRIWKHFORVHGWHVWLQJ SURFHGXUH 7KH FORVHG VHTXHQWLDO WHVWLQJSURFHGXUHDV GHILQHG DERYH PDLQWDLQV WKH RYHUDOO7\SH,HUURURIWKHVWXG\DW &)%LQ8UJHQF\(SLVRGHVDW:HHN ,QWKLVVWXG\WKHQXPEHURIXUJHQF\HSLVRGHVLVGHILQHGDVWKHQXPEHURIWLPHVDSDWLHQW KDV PDUNHG WKH ³QHHG WR XULQDWH LPPHGLDWHO\´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ሻ݁ݏܾܽ ሺܽݒ݈ܽ െ ͳͲͲ כ Ψ݄ܿܽ݊݃݁ ൌ ܾܽݏ݁ 3DJHRI Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Where aval is the value at Week 12 and base is the baseline value. The achievement of at least a 75% reduction in UUI episodes (and similarly, a 100% reduction in UUI episodes) is a binary variable of 0 (endpoint is not attained) or 1 (endpoint is attained). The difference in proportion responding between vibegron and placebo, and tolterodine and placebo along with the associated 95% confidence interval and p-value, will be calculated using the Cochran-Mantel-Haenszel risk difference estimate stratified by Sex (Female vs Male)., with weights proposed by Greenland and Robins, which is calculated as follows: ∑𝑢 𝑤 ∙ 훿̂ ̂ 𝑖=1 𝑖 𝑖 훿푀퐻 = 𝑢 , where ∑𝑖=1 𝑤𝑖 𝑥 𝑦 ̂ 𝑖 𝑖 훿𝑖 = − denotes the risk difference in stratum 𝑖, 𝑖 = 1, ⋯ ,𝑢 𝑛𝑖 𝑚𝑖 𝑛𝑖 ∙ 𝑚𝑖 𝑤𝑖 = denotes the weight of stratum 𝑖, 𝑖 = 1, ⋯ ,𝑢 𝑛𝑖 + 𝑚𝑖 𝑥𝑖 denotes the number of patients with event in treatment1in stratum i, 𝑖 = 1, ⋯ , 𝑢 𝑦𝑖 denotes the number of patients with event in treatment2in stratum i, 𝑖 = 1, ⋯ , 𝑢 𝑛𝑖 denotes the number of patients on treatment1in stratum i, 𝑖 = 1, ⋯ , 𝑢 𝑚𝑖 denotes the number of patients on treatment2in stratum i, 𝑖 = 1, ⋯ , 𝑢 ̂ The estimated variance of 훿푀퐻 is calculated as: ∑𝑢 퐿 ̂ 𝑖=1 𝑖 𝑣̂𝑎𝑟 (훿푀퐻) = 𝑢 2 (∑𝑖=1 𝑤𝑖) 3 3 𝑥𝑖(𝑛𝑖 − 𝑥𝑖) 𝑚𝑖 + 𝑦𝑖(𝑚𝑖 − 𝑦𝑖) 𝑛𝑖 where 퐿𝑖 = 2 , 𝑖 = 1, ⋯ , 𝑢 𝑛𝑖 ∙ 𝑚𝑖 ∙ (𝑛𝑖 + 𝑚𝑖) ̂ Assuming a normal distribution of 훿푀퐻 , an approximate 95% CI is given as follows, where 𝑧0.975 is the 97.5% quantile of the standard normal distribution: ̂ ̂ 𝐶퐼 = [훿푀퐻 ± 𝑧0.975 ∙ √𝑣𝑎𝑟̂(훿푀퐻)] Also, the approximate p-value can be calculated using the following: Page 51 of 88 51 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 ̂ 훿푀퐻 pvalue = 2 ∙ Pr 𝑍 > | | , where 𝑍 ~ 푁(0, 1) √𝑣𝑎𝑟̂(훿̂ ) [ 푀퐻 ] If there is a stratum for a treatment group that has 0 patients in it, the 0 count will be replaced by 0.5 in order to prevent dividing by 0 in the above equations, as suggested in Greenland & Robins. The primary inference will be drawn from the treatment difference between vibegron and placebo at Week 12. The table output will show the number and percent of patients attaining the endpoint for all treatment arms, the CMH estimated risk difference between vibegron and placebo, and tolterodine and placebo with 95% CI and p-value using the above formula at Week 12. The table output will also include this summary at Weeks 2, 4, and 8. To further characterize meaningful change from baseline at Week 12 in urgency episodes as defined by various anchor levels of PGI-Severity, PGI-Control, and PGI-Frequency. Cumulative function (CDF) plots and kernel density plots of percent change from baseline at Week 12 in average daily urgency episodes will be categorized by the following anchor levels. The anchor levels of PGI-Severity, PGI-Control, and PGI-Frequency are shifts from baseline to Week 12, separately. The number of patients and mean percent CFB at Week 12 in average daily urgency episodes will be presented on the plots. ≥2 categories worse One-category worse No change One-category improvement Two-categories improvement ≥3 categories improvement To further evaluate clinical meaningful improvement in the PGI-Control and PGI- Frequency items, the described CDF and kernel density plots will be provided for the subset of patients with severe symptoms at baseline (e.g., patients with “no control” over OAB symptoms’ in PGI-Control; patients experiencing OAB symptoms “very often” in PGI-Frequency). These are further described in the Exploratory Efficacy Endpoints section. Page 52 of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³$FFLGHQWDO8ULQH/HDNDJH´DQGRU ³$FFLGHQWDO8ULQH/HDNDJH´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tatistical Analysis Plan Urovant Protocol #3003 Version 3.1 populations, and there is strong evidence to support the measure’s content validity in both target patient populations. In addition, the OAB-q has been shown to have excellent measurement properties, including validity and reliability. See Appendix 2 for a complete list of questions. The first 8 questions of the OAB-q LF ask patients much they are bothered by their bladder symptoms during the last week. Each question has a response ranging from “Not at all” which is scored as a 1 to “A very great deal” which is scored as a 6. These questions make up the symptom bother scale. Questions 9 through 33 ask patients how much their symptoms have affected their life over the last week. Each question has a response ranging from “None of the time” which is scored as a 1 to “All of the time” which is scored as a 6. There are 4 subscales and one total score derived from these questions as follows: To transform the raw scores to a unified score ranging from 0 to 100, the following algorithms are used. For the Symptom Bother Score, the transformed score is: (𝑎𝑐𝑡𝑢𝑎푙 𝑠𝑐𝑜𝑟푒−푙𝑜푤푒𝑠𝑡 𝑝𝑜𝑠𝑠𝑖𝑏푙푒) (𝑎𝑐𝑡𝑢𝑎푙 𝑠𝑐𝑜𝑟푒−8) 𝑠𝑐𝑜𝑟𝑒 = = 𝑟𝑎𝑛𝑔푒 40 x 100 For Symptom Bother, higher scores correspond to the symptoms having a larger bother and lower scores represent a lower amount of bother due to symptoms. 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An AE will be considered treatment emergent (TEAE) if it begins or worsens in severity after the first dose of the double-blind Study Treatment through 28 days after the last dose of Study Treatment, or the date of initiation of another investigational agent or surgical intervention or rollover to the extension study, whichever occurs first. Partial AE start dates will be imputed as detailed in Section 6.4. A Serious Adverse Event (SAE) is any untoward medical occurrence that: Results in death Is life-threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Is another medically important condition In addition, any illnesses reported before starting active treatment or AE meeting the criteria of seriousness (as defined above) and considered to be possibly related (according to the Investigator) to any study-specific procedure (e.g., laboratory testing procedure, liver biopsy) must be reported as an SAE. Summary tables will be based on treatment emergent adverse events (TEAEs). The incidence of TEAEs will be presented using counts and percentages of patients with TEAEs and tabulated by SOC and PT. SOC will be sorted in descending frequency and PT within SOC will be sorted by descending frequency based on the incidence across patients overall. If a patient has multiple occurrences (start and stop) of an event associated with a specific SOC or PT within a SOC, a patient will only be counted once in the incidence count for the SOC or PT within SOC respectively. An overall summary table of AEs by treatment group will be presented detailing the number and percentage of patients, and number of events for the following categories: At least one TEAE; At least one Treatment-Related TEAE; At least one Grade ≥ 3 TEAE; At least one Grade ≥ 3 Treatment-Related TEAE; At least one Serious TEAE; At least one Serious Treatment-Related TEAE; At least one TEAE leading to Discontinuation from Study Medication; Page 64 of 88 64 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 At least one TEAE of Clinical Interest; At least one Treatment-Related TEAE of Clinical Interest The incidence of all TEAEs by SOC and PT will be presented for the following: All TEAEs; Treatment-Related TEAEs; TEAES with Grade ≥ 3; Serious TEAEs; Serious TEAEs with Grade ≥ 3; Treatment Related Serious TEAEs; TEAEs leading to Discontinuation from Study Treatment; Non-Serious TEAEs ≥ 5% Threshold Non-fatal TEAEs Hypertension TEAEs by Pre-existing Hypertension (Yes vs No) and Baseline Hypertension (Yes vs. No). Hypertension TEAEs will be selected as any TEAE with Preferred Term of Hypertension. Treatment listings will include the treatment arm, start and stop dates/times of the AE, and days on study relative to the day of first dose of study treatment. A Treatment related AE is defined as an AE for which the investigator classifies the AE as being related to study treatment. To be conservative, the summary table will include events where the relationship to study treatment is missing. Missing severity for TEAEs will be counted as ‘Severe’. For the Non-Serious TEAEs ≥ 5% Threshold, it will include adverse events if the event occurs at an incidence of greater than or equal to 5% in any treatment arm. No rounding is allowed. If an adverse event occurs at an incidence of 4.8%, for example, the incidence will not be rounded up to 5% for the purposes of this table. Treatment Emergent Adverse Events of Clinical Interest (AECI) and Treatment-Related TEAEs of Clinical Interest will also be summarized by SOC and PT. Adverse Events of Clinical Interest for this study include: Potential Major Adverse Cardiac and Cerebrovascular Events (MACCE), which will be adjudicated by an independent external expert clinical adjudication committee (CAC) into the following categories according to the definitions in the CAC Charter: o Death or any event with fatal outcome o Myocardial infarction / Heart Attack o Cerebrovascular Accident / Stroke Page 65 of 88 65 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 o Hospitalization for Unstable Angina / Chest Pain o Hospitalization for Heart Failure o Coronary revascularization / Angioplasty / Stent Hypertension: An adverse event of hypertension should be reported and will be an AECI as follows: o For patients without hypertension (average SBP <140 mmHg, DBP <90 mmHg) at baseline, at two consecutive visits, the average of three systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg (or both); at 2 consecutive visits in patients who were not hypertensive at baseline; or, o For patients with hypertension at baseline, an increase compared to baseline at 2 consecutive visits in the average of three SBP by ≥20 mmHg OR DBP by ≥10 mmHg; o Initiation of, or increase in dose of, medication for treatment of hypertension in any patient. Adverse events consistent with orthostatic hypotension as confirmed by orthostatic vital signs. Adverse events suggestive of cystitis or urinary tract infection. Elevated AST or ALT lab value requiring that study drug be temporarily withheld or permanently discontinued (see Section 8.6.1 and Section 8.6.2). The following additional listings will be provided: Listing of deaths Listing of Serious TEAEs Listing of non-treatment-emergent SAEs Listing of TEAEs leading to withdrawal or temporary withdrawal of study treatment Listing of all AEs with a flag for TEAEs and onset (Prior = prior to first dose of single- blind medication, Run-in = on or after first dose of single-blind medication but prior to first dose of double-blind medication, or Treatment = on or after first dose of double- blind medication.) A summary of all TEAEs by maximum intensity (mild, moderate, severe, life-threatening, death), SOC, and PT will be presented, where the maximum intensity per patient will be counted at each level of summarization. In addition, a summary of all TEAEs by relationship to study treatment (related, not related), SOC and PT will be presented, where all relationships to study treatment per patient will be counted at each level of summarization. A summary of all TEAEs by PT occurring in at least 2% of patients in the Page 66 of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ȕK&* 2WKHU 6HUXPȕKXPDQFKRULRQLFJRQDGRWURSLQ ȕK&* ZKHUHDSSOLFDEOH D$VDPSOHIRUXULQDO\VLVDQGXULQHFXOWXUHZLOOEHVHQWWRWKHFHQWUDOODERUDWRU\RQO\LIWKHXULQHGLSVWLFNSHUIRUPHGDWWKHVLWHWHVWV SRVLWLYHIRUWKHSUHVHQFHRIOHXNRF\WHVQLWULWHVRUEORRGFHOOV E8ULQHȕK&*ZLOOEHWHVWHGIRUZRPHQRIFKLOGEHDULQJSRWHQWLDORQO\,IXULQHȕK&*LVSRVLWLYHDVHUXPȕ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x 6%3 PP+J x '%3 PP+J x 3XOVH5DWH EHDWVPLQ x 5HVSLUDWLRQ5DWH x 7HPSHUDWXUH x :HLJKW .J x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tatistical Analysis Plan Urovant Protocol #3003 Version 3.1 10. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL The following changes to the analyses specified in the Protocol are enacted. Where specified, the section relates to the section of the SAP. Page 70 of 88 70 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 11. REFERENCE LIST 1. Coyne KS, Gelhorn H, Thompson C, Kopp ZS, Guan Z.The psychometric validation of a 1-week recall period for the OAB-q. Int Urogynecol J. 2011;22(12):1555-1563. 2. Matza LS, Thompson C L, Krasnow J, Brewster-Jordan J, Zyczynski T, Coyne K S. Test-retest reliability of four questionnaires for patients with overactive bladder: The overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ). Neurourol. Urodyn. 2005; 24(3): 215–225. 3. REILLY ASSOCIATES. (2017). WPAI Scoring. Available: http://www.reillyassociates.net/WPAI_Scoring.html . Last accessed 08/28/2017. 4. EuroQol. (2017). EQ-5D Instruments | About EQ-5D. Available: https://euroqol.org/. Last accessed 08/28/2017. 5. Coyne KS, Thompson CL, Lai JS, Sexton C. An Overactive Bladder Symptom and Health-Related Quality of Life Short-Form: Validation of the OAB-q SF. Neurourology and Urodynamics 34:255–263 (2015) Page 71 of 88 71 6WDWLVWLFDO$QDO\VLV3ODQ 8URYDQW3URWRFRO 9HUVLRQ 352*5$00,1*&216,'(5$7,216 $OO WDEOHV GDWD OLVWLQJV ILJXUHV 7/)V DQG VWDWLVWLFDO DQDO\VHV ZLOO EH JHQHUDWHG XVLQJ 6$6 IRU :LQGRZV 5HOHDVH 6$6 ,QVWLWXWH ,QF &DU\ 1& 86$ &RPSXWHU JHQHUDWHGWDEOHOLVWLQJDQGILJXUHRXWSXWZLOODGKHUHWRWKHIROORZLQJVSHFLILFDWLRQV *HQHUDO&RQVLGHUDWLRQV x 2QH6$6SURJUDPFDQFUHDWHVHYHUDORXWSXWV x (DFKRXWSXWZLOOEHVWRUHGLQDVHSDUDWHILOH x 2XWSXWILOHVZLOOEHGHOLYHUHGLQUWIIRUPDW x 1XPEHULQJRI7)/VZLOOIROORZ,&+(JXLGDQFH 7DEOH/LVWLQJDQG)LJXUH)RUPDW *HQHUDO x $OO7/)VZLOOEHSURGXFHGLQODQGVFDSHIRUPDWXQOHVVRWKHUZLVHVSHFLILHG x $OO7/)VZLOOEHSURGXFHGXVLQJWKH&RXULHU1HZIRQWVL]H x 7KHGDWDGLVSOD\VIRUDOO7/)VZLOOKDYHDPLQLPXPLQFKPDUJLQRQDOOVLGHV x +HDGHUVDQGIRRWHUVIRUILJXUHVZLOOEHLQ&RXULHU1HZIRQWVL]H x /HJHQGV ZLOO EH XVHG IRU DOO ILJXUHV ZLWK PRUH WKDQ YDULDEOH JURXS RU LWHP GLVSOD\HG x 7/)VZLOOEHLQEODFNDQGZKLWH QRFRORU XQOHVVRWKHUZLVHVSHFLILHG x 6SHFLDOL]HGWH[WVW\OHVVXFKDVEROGLQJLWDOLFVERUGHUVVKDGLQJDQGVXSHUVFULSWHGDQG VXEVFULSWHG WH[W ZLOO QRW EH XVHG LQ WKH 7/)V XQOHVV RWKHUZLVH VSHFLILHG 2Q VRPH RFFDVLRQVVXSHUVFULSWVRUPD\EHXVHG VHHEHORZ x 2QO\VWDQGDUGNH\ERDUGFKDUDFWHUVZLOOEHXVHGLQWKH7/)V6SHFLDOFKDUDFWHUVVXFKDV QRQSULQWDEOHFRQWUROFKDUDFWHUVSULQWHUVSHFLILFRUIRQWVSHFLILFFKDUDFWHUVZLOOQRWEH XVHG +H[DGHFLPDOGHULYHG FKDUDFWHUV ZLOO EH XVHG ZKHUH SRVVLEOH LI WKH\ DUH DSSURSULDWHWRKHOSGLVSOD\PDWKV\PEROV HJȝ &HUWDLQVXEVFULSWVDQGVXSHUVFULSWV HJFP&PD[ ZLOOEHHPSOR\HGRQDFDVHE\FDVHEDVLV 3DJHRI 6WDWLVWLFDO$QDO\VLV3ODQ 8URYDQW3URWRFRO 9HUVLRQ x 0L[HG FDVH ZLOO EH XVHG IRU DOO WLWOHV IRRWQRWHV FROXPQ KHDGHUV DQG SURJUDPPHU VXSSOLHGIRUPDWVDVDSSURSULDWH +HDGHUV x $OO RXWSXW VKRXOG KDYH WKH IROORZLQJ KHDGHU DW WKH WRS OHIW RI HDFK SDJH 8URYDQW6FLHQFHV3URWRFRO597 x $OO RXWSXW VKRXOG KDYH 3DJH Q RI 1 DW WKH WRS RU ERWWRP ULJKW FRUQHU RI HDFK SDJH 7/)VVKRXOGEHLQWHUQDOO\SDJLQDWHGLQUHODWLRQWRWKHWRWDOOHQJWK LHWKHSDJHQXPEHU VKRXOGDSSHDUVHTXHQWLDOO\DVSDJHQRI1ZKHUH1LVWKHWRWDOQXPEHURISDJHVLQWKH WDEOH x 7KHGDWHRXWSXWZDVJHQHUDWHGVKRXOGDSSHDUDORQJZLWKWKHSURJUDPQDPHDVDIRRWHU RQHDFKSDJH 'LVSOD\7LWOHV x (DFK7/)VKRXOGEHLGHQWLILHGE\WKHGHVLJQDWLRQDQGDQXPHUDO LH7DEOH ,&+ ( QXPEHULQJ LV VWURQJO\ UHFRPPHQGHG EXW VSRQVRU SUHIHUHQFHV VKRXOG EH REWDLQHG SULRU WR ILQDO GHWHUPLQDWLRQ VHH DOVR WHPSODWH & ³7DEOH RI &RQWHQWV IRU7DEOHV/LVWLQJVDQG)LJXUHVLQ6WDWLVWLFDO$QDO\VLV3ODQ´ $GHFLPDOV\VWHP [\ DQG[\] VKRXOGEHXVHGWRLGHQWLI\7/)VZLWKUHODWHGFRQWHQWV7KHWLWOHLVFHQWHUHG 7KHDQDO\VLVVHWVKRXOGEHLGHQWLILHGRQWKHOLQHLPPHGLDWHO\IROORZLQJWKHWLWOH7KH WLWOH DQG WDEOH GHVLJQDWLRQ DUH VLQJOH VSDFHG $ VROLG OLQH VSDQQLQJ WKH PDUJLQV ZLOO VHSDUDWHWKHGLVSOD\WLWOHVIURPWKHWDEOHFRQWHQWV x &ROXPQKHDGHUV7KHUHZLOOEHEODQNOLQHEHWZHHQWKHODVWWLWOHDQGWKHVROLGOLQH 7DEOH[\] )LUVW/LQHRI7LWOH 6HFRQG/LQHRI7LWOHLI1HHGHG ,77$QDO\VLV6HW &ROXPQ+HDGHUV x &ROXPQ KHDGLQJV VKRXOG EH GLVSOD\HG LPPHGLDWHO\ EHORZ WKH VROLG OLQH GHVFULEHG DERYHLQLQLWLDOXSSHUFDVHFKDUDFWHUV x ,QWKHFDVHRIHIILFDF\WDEOHVWKHYDULDEOH RUFKDUDFWHULVWLF FROXPQZLOOEHRQWKHIDU OHIWIROORZHGE\WKHWUHDWPHQWJURXSFROXPQVDQGWRWDOFROXPQ LIDSSOLFDEOH 3YDOXHV 3DJHRI 6WDWLVWLFDO$QDO\VLV3ODQ 8URYDQW3URWRFRO 9HUVLRQ PD\EHSUHVHQWHGXQGHUWKHWRWDOFROXPQRULQVHSDUDWHSYDOXHFROXPQ LIDSSOLFDEOH :LWKLQWUHDWPHQW FRPSDULVRQV PD\ KDYH SYDOXHV SUHVHQWHG LQ D URZ EHQHDWK WKH VXPPDU\VWDWLVWLFVIRUWKDWWUHDWPHQW x )RUQXPHULFYDULDEOHVLQFOXGH³XQLW´LQFROXPQRUURZKHDGLQJZKHQDSSURSULDWH x $QDO\VLVVHWVL]HVZLOOEHSUHVHQWHGIRUHDFKWUHDWPHQWJURXSLQWKHFROXPQKHDGLQJDV 1 [[ RULQWKHURZKHDGLQJVLIDSSOLFDEOH 7KLVLVGLVWLQFWIURPWKHµQ¶XVHGIRUWKH GHVFULSWLYHVWDWLVWLFVUHSUHVHQWLQJWKHQXPEHURISDWLHQWVLQWKHDQDO\VLVVHW x 7KHRUGHURIWUHDWPHQWVLQWKHWDEOHVDQGOLVWLQJVZLOOEHSODFHERYLEHJURQWROWHURGLQH IROORZHGE\DWRWDOFROXPQ LIDSSOLFDEOH %RG\RIWKH'DWD'LVSOD\ *HQHUDO&RQYHQWLRQV 'DWDLQFROXPQVRIDWDEOHRUOLVWLQJVKRXOGEHIRUPDWWHGDVIROORZV x $OSKDQXPHULFYDOXHVDUHOHIWMXVWLILHG x :KROHQXPEHUV HJFRXQWV DUHULJKWMXVWLILHG DQG x 1XPEHUVFRQWDLQLQJIUDFWLRQDOSRUWLRQVDUHGHFLPDODOLJQHG 7DEOH&RQYHQWLRQV x 8QLWVZLOOEHLQFOXGHGZKHUHDYDLODEOH x ,IWKHFDWHJRULHVRIDSDUDPHWHUDUHRUGHUHGWKHQDOOFDWHJRULHVEHWZHHQWKHPD[LPXP DQGPLQLPXPFDWHJRU\VKRXOGEHSUHVHQWHGLQWKHWDEOHHYHQLIQ IRUDOOWUHDWPHQW JURXSVLQDJLYHQFDWHJRU\WKDWLVEHWZHHQWKHPLQLPXPDQGPD[LPXPOHYHOIRUWKDW SDUDPHWHU)RUH[DPSOHWKHIUHTXHQF\GLVWULEXWLRQIRUV\PSWRPVHYHULW\ZRXOGDSSHDU DV 6HYHULW\ 1 5DWLQJ VHYHUH PRGHUDWH PLOG :KHUH SHUFHQWDJHV DUH SUHVHQWHG LQ WKHVH WDEOHV ]HUR SHUFHQWDJHV ZLOO QRW EH SUHVHQWHGDQGVRDQ\FRXQWVRIZLOOEHSUHVHQWHGDVDQGQRWDV 3DJHRI Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, etc.), then only those categories for which there is at least 1 patient represented in 1 or more groups should be included. An Unknown or Missing category should be added to any parameter for which information is not available for 1 or more patients. Unless otherwise specified, the estimated mean and median for a set of values should be printed out to 1 more significant digit than the original values, and standard deviations should be printed out to 2 more significant digits than the original values. The minimum and maximum should report the same significant digits as the original values. For example, for systolic blood pressure: N XX Mean XXX.X Std Dev X.XX Median XXX.X Minimum XXX Maximum XXX P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-value should be less than 0.0001 then present as <0.0001. If the p-value is returned as >0.999 then present as >0.999 Percentage values should be printed to one decimal place, in parentheses with no spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to display values that round down to 0.0. A common convention is to display as '<0.1', or as appropriate with additional decimal places. Unless otherwise noted, for all percentages, the number of patients in the analysis set for the treatment group who have an observation will be the denominator. Percentages after zero counts should not be displayed and percentages equating to 100% should be presented as 100%, without any decimal places. Page 75 of 88 75 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Tabular display of data for medical history, prior / concomitant medications, and all tabular displays of adverse event data should be presented by the body system, treatment class, or SOC with the highest occurrence over all treatment groups in decreasing order, assuming all terms are coded. Within the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), and adverse events (by preferred term) should be displayed in decreasing order. If incidence for more than 1 term is identical, they should then be sorted alphabetically. Missing descriptive statistics or p-values which cannot be estimated should be reported as “-”. The percentage of patients is normally calculated as a proportion of the number of patients assessed in the relevant treatment group (or overall) for the analysis set presented. However, careful consideration is required in many instances due to the complicated nature of selecting the denominator, usually the appropriate number of patients exposed. Describe details of this in footnotes or programming notes. For categorical summaries (number and percentage of patients) where a patient can be included in more than one category, describe in a footnote or programming note if the patient should be included in the summary statistics for all relevant categories or just 1 category and the criteria for selecting the criteria. Where a category with a subheading (such as system organ class) has to be split over more than one page, output the subheading followed by “(cont)” at the top of each subsequent page. The overall summary statistics for the subheading should only be output on the first relevant page. 12.2.5.3. Listing Conventions Listings will be sorted for presentation in order of treatment groups as above, patient number, visit/collection day, and visit/collection time. Missing data should be represented on patient listings as either a hyphen (“-”) with a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, whichever is appropriate. Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates should be represented on patient listings as dashes (-- JUL2000). Dates that are missing because they are not applicable for the patient are output as “N/A”, unless otherwise specified. All observed time values must be presented using a 24-hour clock HH:MM or HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. Units will be included where available Page 76 of 88 76 6WDWLVWLFDO$QDO\VLV3ODQ 8URYDQW3URWRFRO 9HUVLRQ )LJXUH&RQYHQWLRQV x 8QOHVVRWKHUZLVHVSHFLILHGIRUDOOILJXUHVVWXG\YLVLWVZLOOEHGLVSOD\HGRQWKH;D[LV DQGHQGSRLQW HJWUHDWPHQWDYHUDJHFKDQJHIURP%DVHOLQH YDOXHVZLOOEHGLVSOD\HG RQWKH<D[LV )RRWQRWHV x $VROLGOLQHVSDQQLQJWKHPDUJLQVZLOOVHSDUDWHWKHERG\RIWKHGDWDGLVSOD\IURPWKH IRRWQRWHV x $OOIRRWQRWHVZLOOEHOHIWMXVWLILHGZLWKVLQJOHOLQHVSDFLQJLPPHGLDWHO\EHORZWKHVROLG OLQHXQGHUQHDWKWKHGDWDGLVSOD\ x )RRWQRWHVVKRXOGDOZD\VEHJLQZLWK³1RWH ´LIDQLQIRUPDWLRQDOIRRWQRWHRUHWF LIDUHIHUHQFHIRRWQRWH(DFKQHZIRRWQRWHVKRXOGVWDUWRQDQHZOLQHZKHUHSRVVLEOH x 3DWLHQWVSHFLILFIRRWQRWHVVKRXOGEHDYRLGHGZKHUHSRVVLEOH x )RRWQRWHVZLOOEHXVHGVSDULQJO\DQGPXVWDGGYDOXHWRWKHWDEOHILJXUHRUGDWDOLVWLQJ ,I PRUH WKDQ VL[ OLQHV RI IRRWQRWHV DUH SODQQHG WKHQ D FRYHU SDJH PD\ EH XVHG WR GLVSOD\ IRRWQRWHV DQG RQO\ WKRVH HVVHQWLDO WR FRPSUHKHQVLRQ RI WKH GDWD ZLOO EH UHSHDWHGRQHDFKSDJH x 7KHODVW OLQHRIWKHIRRWQRWH VHFWLRQZLOOEHDVWDQGDUGVRXUFHOLQHWKDW LQGLFDWHVWKH QDPHRIWKHSURJUDPXVHGWRSURGXFHWKHGDWDGLVSOD\GDWHWKHSURJUDPZDVUXQDQG WKHOLVWLQJVRXUFH LHµ3URJUDP P\SURJUDPVDV/LVWLQJVRXUFH [\]¶ 3DJHRI Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 13. QUALITY CONTROL SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, figures or statistical analyses. provide an overview of the development of such SAS programs. describes the quality control procedures that are performed for all SAS programs and output. Quality control is defined here as the operational techniques and activities undertaken to verify that the SAS programs produce the output by checking for their logic, efficiency and commenting and by review of the produced output. Page 78 of 88 78 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 14. APPENDICES Page 79 of 88 79 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Page 80 of 88 80 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Appendix 2: OAB-q-1 wk English-US-original Page 81 of 88 81 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Page 82 of 88 82 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Page 83 of 88 83 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Appendix 3: Global Impression Items Patient Global Impression of Severity (PGI-Severity) 1. Over the past week, how would you rate your overactive bladder symptoms? None Mild Moderate Severe Patient Global Impression of Control (PGI-Control) 2. Over the past week, how much control did you have over your overactive bladder symptoms? Complete control A lot of control Some control Only a little control No control Patient Global Impression of Symptom Frequency (PGI-Frequency) 3. Over the past week, how often did you have overactive bladder symptoms? Never Rarely Sometimes Often Very often Page 84 of 88 84 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Patient Global Impression of Urgency-Related Leakage (PGI-Leakage) 4. Over the past week, how often did you have accidental urine leakage? Never Rarely Sometimes Often Very often Patient Global Impression of Change (PGI-Change) 5. Overall, compared to the start of the study, how would you rate your overactive bladder symptoms over the past week? Much better Moderately better A little better No change A little worse Moderately worse Much worse Page 85 of 88 85 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Appendix 4: Cover Note for Listings For the following listings, the given questions are represented by numbers within the listing. The relevant mapping is shown below. Listing 16.2.6.4 OAB-q LF Questions During the past week, how bothered were you by… 1. Frequent urination during the daytime 2. An uncomfortable urge to urinate? 3. A sudden Urge to Urinate with little or no warning 4. Accidental loss of small amounts of urine? 5. Nighttime urination? 6. Waking up at night because you had to urinate? 7. An uncontrollable urge to urinate? 8. Urine loss associated with a strong desire to urinate? During the past week how often have your bladder symptoms… 9. Made you carefully plan your commute? 10. Caused you to feel drowsy or sleepy during the day? 11. Caused you to plan “escape routes” to restrooms in public places? 12. Caused you distress? 13. Frustrated you? 14. Made you feel like there is something wrong with you? 15. Interfered with your ability to get a good night’s rest? 16. Caused you to decrease your physical activities (exercising, sports, etc.)? 17. Prevented you from feeling rested upon waking in the morning? 18. Frustrated your family and friends? 19. Caused you anxiety or worry? 20. Caused you to stay home more often than you would prefer? 21. Caused you to adjust your travel plans so that you are always near a restroom? 22. Made you avoid activities away from restrooms (i.e., walks, running, hiking)? 23. Made you frustrated or annoyed about the amount of time you spend in the restroom? 24. Awakened you during sleep? 25. Made you worry about odor or hygiene? 26. Made you uncomfortable while traveling with others because of needing to stop for a restroom? 27. Affected your relationships with family and friends? 28. Caused you to decrease participating in social gatherings, such as parties or visits with family or friends? 29. Caused you embarrassment? 30. Interfered with getting the amount of sleep you needed? 31. Caused you to have problems with your partner or spouse? 32. Caused you to plan activities more carefully? 33. Caused you to locate the closest restroom as soon as you arrive at a place you have never been? Page 86 of 88 86 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Listing 16.2.6.4 EQ-5D Answers Mobility 1. I have no problems walking about 2. I have some problems walking about 3. I am confined to bed Self-Care 4. I have problems with self-care 5. I have some problems with washing or dressing myself 6. I am unable to wash or dress myself Usual Activities 1. I have no problems with performing my usual activities 2. I have some problems with performing my usual activities 3. I am unable to perform my usual activities Pain/ Discomfort 1. I have no pain or discomfort 2. I have moderate pain or discomfort 3. I have extreme pain or discomfort Anxiety/ depression 1. I am not anxious or depressed 2. I am moderately anxious or depressed 3. I am extremely anxious or depressed Page 87 of 88 87 Statistical Analysis Plan Urovant Protocol #3003 Version 3.1 Page 88 of 88 88