Study No.: AVO112760 Title: A Observatioal Study To Assess The Burde Of Illess I Prostate Cacer Patiets With Low To Moderate Risk Of Progressio Ratioale: Little data are available o the burde of illess i me diagosed with low-to-moderate risk prostate cacer i relatio to ay adverse impact o quality of life (QoL), o axiety ad depressio, ad o the ecoomic cost to society ad health care providers. Therefore, the impact of the various treatmet optios available o both the subject, society ad health care providers is worthy of evaluatio. This prospective observatioal study was desiged to assess the medical ad ecoomic burde of prostate cacer with low-to-moderate risk of progressio durig the first year of diagosis from a Europea perspective. Phase: IV Study Period: 25Ju2009 to 27Sep2011 Study Desig: This was a prospective, 1-year observatioal, pa-europea study i subjects with low-to-moderate risk prostate cacer. Quality of life, overall health status, axiety ad depressio, ad costs i relatio to their prostate cacer diagosis ad disease maagemet were assessed withi 2 moths after diagosis ad prostate cacer treatmet started. The assessmets were also made at 3 moths ad at 12 moths after treatmet started. The study aimed to collect a measure of the subjects QoL without ay itervetio i the subjects healthcare regime. The followig questioaires were used: QLQ-PR25 ad QLQ-C30 to assess subjects quality of life related to their prostate cacer EQ-5D to assess overall health status The Hospital Axiety ad Depressio Scale (HADS) to evaluate axiety ad depressio Cost related assessmets: The Work Productivity Assessmet Idex (WPAI) to capture idirect costs associated with prostate cacer treatmet Direct costs assessed from actual prostate cacer treatmets ad resource utilizatio as recorded i the case report form Cetres: A total of 68 cetres i 5 coutries erolled subjects i the study: 20 i Germay, 19 i Frace, 11 i Spai, 9 each i Italy ad Swede. Idicatio: Prostate cacer Treatmet: No study medicatio was provided by the sposor GlaxoSmithKlie. Objectives: The objectives of this study i subjects with low-to-moderate risk prostate cacer were: Primary: To assess the chage o the subject s quality of life betwee diagosis ad the first 3 moths of treatmet. Secodary: To assess the subject s QoL at diagosis ad withi the first year of treatmet. To assess the impact o axiety/depressio at diagosis ad withi the first year of treatmet. To estimate health care cosumptio ad utility values withi the first year of diagosis. To describe the profile ad medical maagemet from 5 coutries (Frace, Germay, Italy, Spai, ad Swede) i the Europea Uio (EU). Primary Outcome/Efficacy Variable: Chage i QLQ-PR25 uriary symptoms subscale scores from baselie to approximately 3 moths post first treatmet of prostate cacer start. Secodary Outcome/Efficacy Variable(s): Chage i other QLQ-PR25 subscale scores from baselie to approximately 3 moths post first treatmet of prostate cacer start. Chage i all QLQ-PR25 subscale scores from baselie to 12 moths post first treatmet of prostate cacer start. Chage i QLQ-C30 scores from baselie to 3 moths ad to 12 moths post first treatmet of prostate cacer start. Differece i EQ-5D scores ad ormative data at baselie Chage i EQ-5D scores at 3 moths post first treatmet ad to withi 12 moths post first treatmet start for prostate cacer. Differece i HADS scores ad ormative data at baselie Chage i HADS scores from baselie to 3 moths ad to 12 moths post first treatmet of prostate cacer start. Cost assessmet for prostate cacer subjects based o type of treatmet admiistered, resource utilizatio 1
(visits/treatmet) ad idirect costs captured usig the WPAI. Statistical Methods: Oe hudred ad thirty-four subjects were eeded per coutry to have the power of 90% to detect a differece of 4.9 from baselie to 3 moths post first treatmet of prostate cacer start. A repeated measures aalysis of variace was used to assess chages over time for the study edpoits (QLQ-PR25 scores, QLQ-C30 scores, EQ-5D scores, ad HADS scores). Aalyses were doe adjustig for age, cetre, iitial treatmet received, Gleaso score, T-stage, prostate-specific atige (PSA) test result, educatio status ad whether the subject had a Beig Prostatic Hyperplasia (BPH) diagosis or a progressive BPH diagosis (defied by acute uriary retetio (AUR)/BPH surgery). The followig additioal covariates were also icluded i the model if they had a p-value less tha or equal to 0.05 whe added to the model: ethicity; geographic acestry; family history of breast cacer; ad family history of prostate cacer. Two-sided 95% cofidece itervals for the adjusted mea chage from baselie were costructed ad preseted alogside sigificace tests that the adjusted mea chage from baselie was equal to zero. A sigificace level of 0.05 was used for all tests. The EQ-5D ad HADS scores were assessed by calculatig differeces betwee the observed values ad ormal data from the appropriate age ad coutry specific table. A uadjusted mea ad two-sided 95% cofidece iterval was costructed from these differeces, ad a p-value costructed to test whether the mea differece was equal to zero. Ay medical itervetios that the subjects received were summarized based o subjects respodig to each category of the WPAI. There were 2 populatios: The Full Aalyses Set (FAS) cosisted of all subjects who completed the baselie ad the 3 moth QLQ-PR25 questioaires ad FAS was used for aalyses of QLQ-PR25 scores, QLQ-C30 scores, EQ-5D scores, ad HADS scores. The Baselie Aalyses Set (BAS) cosisted of all subjects who completed the baselie EQ-5D ad HADS questioaire. Two datasets were aalysed a observed cases (OC) dataset, ad a additioal dataset that imputed for missig values the last o-missig post-baselie results where they are available (last observatio carried forward; LOCF) e.g. a 3 moth assessmet may be imputed for a missig 12 moth assessmet. The OC results were cosidered the primary aalysis. No efficacy data were collected for the study. No efficacy aalyses were performed. No adverse evets ad serious adverse evets data were collected ad o aalyses were performed. If ay subject experieced a drug-related adverse evet for ay cocomitat medicatio they were take, the ivestigator reported the evet to the maufacturer of the medicatio accordig to local guidelies. Study Populatio: Number (%) of Subjects Etered, N 672 Baselie Aalysis Set 603 (90%) Full Aalysis Set 404 (60%) Completed 597 (89%) Total Number Subjects Withdraw 66 (10%) Lost to follow-up 24 (4%) Coset withdraw 18 (3%) Withdraw due to Protocol Deviatio 16 (2%) Withdraw due to Adverse Evets 4 (<1%) Withdraw due to Study closed/termiated 4 (<1%) Demographics N=603 Males 603 Age (years), Mea±SD 65.0±5.73 Race, (%) Hispaic or Latio 35 (6%) Not Hispaic or Latio 474 (79%) 2
Missig 94 (16%) Family History of Prostate Cacer, (%) 104 (17%) Family History of Breast Cacer, (%) 60 (10%) Total Gleaso Score, (%) 6 400 (66%) 7 203 (34%) Prostate-specific atige (g/ml) Mea±SD 7.207±3.4348 Cliical Stagig, (%) T1a 8 (1%) T1b 5 (<1%) T1c 355 (59%) T2a 123 (20%) T2b 112 (19%) Cliical BPH diagosis, (%) Yes 225 (37%) No 378 (63%) Primary Outcome Results: Chage from Baselie to 3 Moths Post Treatmet i QLQ-PR25 Uriary Symptoms Subscale Score Mea±SE Mea Chage from Baselie (95% CI) Baselie 401 14.7±3.01 Moth 3 403 24.1±3.05 9.36 (7.47,11.25) p-value for Chage from Baselie <0.001 Secodary Outcome Results(s): Mea±SE Mea Chage from Baselie (95% CI) Chages from Baselie i QLQ-PR25 Subset Scores Uriary Symptoms Subscale Score Baselie 401 14.7±3.01 Moth 12 326 19.2±3.03 4.43 (2.70, 6.16) Icotiece Aid Problems Baselie 49-0.9±11.18 Moth 3 202 15.0±10.65 15.81 (5.76, 25.85) Moth 12 124 8.8±10.83 9.63 (-1.01,20.27) Bowel Symptoms Baselie 399 6.2±1.53 Moth 3 399 6.8±1.53 0.60 (-0.24, 1.45) Moth 12 318 7.0±1.54 0.84 (-0.14, 1.81) Hormoal Treatmet-Related Symptoms Baselie 371 7.6±1.82 Moth 3 376 13.0±1.85 5.42 (4.40, 6.43) Moth 12 306 12.7±1.85 5.11 (4.00, 6.21) Sexual Fuctioig Baselie 293 79.7±4.62 Moth 3 221 53.1±4.67-26.54 (-30.57,-22.50) Moth 12 194 52.0±4.67-27.67 (-31.43,-23.91) Sexual Activity Baselie 397 33.2±4.75 Moth 3 401 23.0±4.73-10.29 (-12.99, -7.59) Moth 12 323 25.8±4.77-7.39 (-10.34, -4.44) Chages from Baselie i QLQ-C30 Scales Global Health Status / QoL Scale Mea±SE Mea Chage from Baselie (95% CI) 3
Baselie 400 74.2±3.81 Moth 3 401 71.0±3.81-3.19 (-5.26,-1.12) Moth 12 323 74.2±3.82-0.02 (-2.25, 2.22) Physical Fuctioig Scale Baselie 397 90.3±2.24 Moth 3 394 86.5±2.29-3.81 (-5.03,-2.59) Moth 12 322 88.3±2.29-1.95 (-3.18,-0.72) Role Fuctioig Scale Baselie 400 88.2±3.17 Moth 3 400 79.4±3.27-8.81 (-11.05, -6.58) Moth 12 324 84.5±3.24-3.77 (-5.65, -1.88) Emotioal Fuctioig Scale Baselie 396 80.1±3.88 Moth 3 401 83.3±3.86 3.20 (1.26, 5.13) Moth 12 323 86.3±3.84 6.26 (4.37, 8.14) Cogitive Fuctioig Scale Baselie 302 82.5±4.88 Moth 3 305 81.3±4.90-1.21 (-2.92, 0.49) Moth 12 245 81.0±4.89-1.51 (-3.15, 0.13) Social Fuctioig Scale Baselie 399 89.2±3.40 Moth 3 400 82.3±3.45-6.89 (-8.92,-4.85) Moth 12 323 85.4±3.43-3.83 (-5.74,-1.92) Fatigue Scale Baselie 399 12.8±3.47 Moth 3 399 18.0±3.50 5.22 (3.53, 6.90) Moth 12 322 15.5±3.50 2.78 (1.26, 4.30) Nausea ad Vomitig Scale Baselie 402 4.0±1.31 Moth 3 401 4.0±1.29 0.06 (-0.79, 0.92) Moth 12 325 4.2±1.29 0.20 (-0.67, 1.07) Pai Scale Baselie 399 17.9±3.32 Moth 3 400 21.2±3.36 3.36 (1.26, 5.47) Moth 12 326 17.5±3.32-0.38 (-2.06, 1.29) Dyspoea Score Baselie 400 3.9±3.74 Moth 3 389 6.1±3.76 2.15 (0.40, 3.91) Moth 12 322 6.2±3.77 2.28 (0.50, 4.05) Isomia Score Baselie 401 12.4±4.25 Moth 3 401 14.0±4.25 1.60 (-0.81, 4.01) Moth 12 325 13.2±4.28 0.79 (-1.81, 3.39) Appetite Score Baselie 401 7.2±2.49 Moth 3 401 8.5±2.48 1.28 (-0.36, 2.93) Moth 12 325 7.0±2.47-0.18 (-2.03, 1.67) Costipatio Score Baselie 401 8.3±3.21 Moth 3 403 10.2±3.25 1.92 (-0.39, 4.22) Moth 12 326 6.3±3.19-2.02 (-4.12, 0.07) Diarrhea Score 4
Baselie 401 7.5±2.62 Moth 3 403 7.6±2.60 0.07 (-1.60, 1.74) Moth 12 324 7.3±2.63-0.21 (-2.00, 1.58) Fiacial Score Baselie 400 4.9±2.76 Moth 3 401 7.1±2.77 2.26 (0.78, 3.74) Moth 12 325 6.4±2.79 1.57 (-0.17, 3.32) EQ-5D Scores Mea±SE Mea Chage from Baselie (95% CI) EQ-5DINDEX a Baselie 397 0.8±0.03 Moth 3 400 0.8±0.03 0.01 (-0.01, 0.03) Moth 12 323 0.8±0.03 0.02 (-0.01, 0.04) EQ-5DVAS b Baselie 400 73.1±3.13 Moth 3 403 71.5±3.13-1.58 (-3.26, 0.09) Moth 12 324 74.2±3.12 1.16 (-0.53, 2.85) Estimated Mea Differece betwee EQ- 5DVAS Score ad Normative Data at Baselie Mea Differece±SE (95% CI) Baselie 399 0.3±0.8 (-1.3, 2.0) Mea±SE Mea Chage from Baselie (95% CI) HADS Scores Axiety Baselie 395 5.3±0.74 Moth 3 399 4.4±0.74-0.86 (-1.17,-0.54) Moth 12 317 4.3±0.74-1.03 (-1.36,-0.70) Depressio Baselie 398 4.5±0.68 Moth 3 401 4.5±0.68 0.04 (-0.25, 0.33) Moth 12 316 4.4±0.68-0.13 (-0.46, 0.21) Estimated Mea Differece betwee HADS ad Normative Data at Baselie Mea Differece±SE (95% CI) Axiety Baselie 396 0.8±0.2 (0.4, 1.1) Depressio Baselie 399 0.1±0.2 (-0.2, 0.4) WPAI Data Curret Workig Status, Yes/No/Missig, (%) Baselie 403 101 (25%) / 300 (74%) / 2 (<1%) Moth 3 403 78 (19%) / 322 (80%) / 4 (<1%) Moth 12 326 63 (16%) / 262 (65%) /1 (<1%) Hours missed due to prostate cacer Mea±SD Baselie 107 5.9±19.36 Moth 3 85 5.8±13.36 Moth 12 63 1.5±6.26 Hours missed due to other reasos Mea±SD Baselie 104 4.1±13.31 Moth 3 83 4.8±15.88 Moth 12 64 3.7±9.81 Hours worked Mea±SD 5
Baselie 102 32.0±19.67 Moth 3 86 28.9±21.22 Moth 12 62 31.5±17.72 Prostate cacer affectig work productivity scores Mea±SD Baselie 125 1.4±2.32 Moth 3 101 2.4±3.24 Moth 12 89 1.5±2.49 Prostate cacer affectig regular daily activities scores Mea±SD Baselie 397 1.6±2.27 Moth 3 392 2.6±2.79 Moth 12 313 2.0±2.43 Cosultatio Log Data Number (%) of Subjects (N=603) Ay subject cosultatio related to their 578 (96%) prostate cacer maagemet Related to diagosis/moitorig of prostate 567 (94%) cacer To treat prostate cacer 136 (23%) To treat AEs/complicatios resultig from 121 (20%) treatmet of prostate cacer Related to treatmets that may affect 95 (16%) sigs/symptoms of prostate cacer To treat sigs/symptoms of BPH/LUTS ot 48 (8%) attributed to prostate cacer To treat abormal advacemet or a 17 (3%) complicatio of the prostate cacer Prostatic Procedures/Itervetio Log Number (%) of Subjects (N=603) Data Ay subject experiecig procedure 586 (97%) related to their Prostate cacer As part of diagosis/moitorig of prostate 537 (89%) cacer To treat prostate cacer 502 (83%) To treat ay adverse evets/complicatios 100 (17%) resultig from treatmet of prostate cacer Treatmets that might affect 75 (12%) sigs/symptoms of prostate cacer To treat sigs/symptoms of BPH/LUTS ot 66 (11%) attributed to prostate cacer To treat abormal advacemet or a 9 (1%) complicatio of prostate cacer No adverse evets ad serious adverse evets data were collected ad o aalyses were performed. If ay subject experieced a drug-related adverse evet for ay cocomitat medicatio they were take, the ivestigator reported the evet to the maufacturer of the medicatio accordig to local guidelies. Efficacy Results: No efficacy data were collected. No efficacy aalyses were performed as plaed. Coclusio: The results observed from this study i 5 participatig Europea coutries i subjects with low to moderate risk prostate cacer showed that prostate cacer treatmet impacted o various dimesios of QoL. Prostate cacer treatmet was associated with a decrease i uriary ad sexual fuctioig ad icrease i hormoal treatmet related symptoms. With some exceptios, the impact o treatmet-related fuctioig scales ad symptoms teded to be 6
higher at moth 3 ad have some degree of improvemet at moth 12, however ot reachig baselie levels. The data showed that treatmet of prostate cacer had miimal effects o depressio ad o axiety. Workig productivity ad regular daily activities were ot impacted by diagosis ad treatmet of prostate cacer i this populatio. 7