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“Advance”, “Evolve”, “Impact”: un po’ di chiarezza PER LA PRATICA CLINICA

“Advance”, “Evolve”, “Impact”: un po’ di chiarezza PER LA PRATICA CLINICA . Piergiorgio Messa Nephrology, Dialysis and Renal Transplant Milano-Italy. SHPT & Ca/Pi/ VitD assoc . Changes. Muscle-skeletal pain Bone deformities Bone fractures. Bone Disease.

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“Advance”, “Evolve”, “Impact”: un po’ di chiarezza PER LA PRATICA CLINICA

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  1. “Advance”, “Evolve”, “Impact”: un po’ di chiarezza PER LA PRATICA CLINICA Piergiorgio Messa Nephrology, Dialysis and RenalTransplant Milano-Italy

  2. SHPT & Ca/Pi/VitD assoc. Changes Muscle-skeletalpain Bonedeformities Bonefractures Bone Disease

  3. …..uncontrolled SHP leadsto extremely severe bonedisease

  4. Increased Cardio-vascular Mortality Coronaric &Vascular calcifications SHPT & Ca/Pi/VitD assoc. Changes PTX Muscle-skeletalpain Bonedeformities Bonefractures Bone Disease

  5. Therapyfailure in controlling SHP Ca & Pi Undesiredeffects oftherapy (vitD/Ca salts)

  6. Medical intervention Biochemical Control Effects on the target organs/tissues Clinical outcomes fractures PTX CV morbidity & mortality PTH Ca Pi VitD Bone disease PTH gland hypertr. Vasc Calc LVH ADVANCE EVOLVE

  7. ADVANCE STUDY Study Hypothesis A treatment regimen that includes cinacalcetplus low-dose vitamin D will attenuate progression of coronary artery calcification (CAC) over one year, compared with traditional therapy*, in hemodialysis patients treated with calcium-containing phosphate binders or no binders. *Traditional Therapy = vitamin D + phosphate binders (only Ca-containing PBs)

  8. ADVANCE STUDY Floege J et al NDT 2010

  9. Study Endpoints Primary Endpoint Percentage change in CAC score from baseline to Week 52 based on Agatston score • Percentage change from baseline in CAC score at week 52 Secondary Endpoints • Absolute change in CAC score from baseline to Week 52 • Absolute and percentage change in calcification scores for: • Thoracic aorta from baseline to Week 52 • Aortic and mitral valve from baseline to Week 52 • Proportion of patients with > 15% progression of CAC • from baseline to Week 52 • Absolute and percentage change in laboratory • parameters at end of study (weeks 44 to 52) • Safety

  10. Baseline Laboratory Parameters Efficacy Evaluable Analysis Set Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, 2010. Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

  11. Percent Change in Total Coronary Artery Calcification Score (CAC) Primary analysis based on a generalised Cochran-Mantel-Haenszel test on ranks Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, 2010. Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

  12. Median Treatment Differences, All Sites Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, 2010. Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

  13. Weekly Active Vitamin D Dose (IV Paricalcitol Equivalents) by Treatment Group Raggi P et al. Poster presented at the 2010 Clinical Meeting of the National Kidney Foundation, Orlando, FL, April 13-17, 2010. Floege J et al. Poster presented at the 2010 ISN Nexus Meeting, Kyoto, Japan, April 15-18, 2010.

  14. Mean (SE) Daily Calcium-Containing Phosphate Binder Dose by Treatment Group Raggi P et al NDT 2012

  15. limiti • Periodo di studio relativamente breve • End-point primario non del tutto appropriato da un punto di vista metodologico • Studio limitato a pazienti con un CAC score >30 • Uso consentito solo di chelanti contenenti Ca

  16. Suggerimenti • I pazienti con carico di calcificazioni più elevato potrebbero beneficiarne di più • Un periodo più lungo potrebbe dimostrare maggiori benefici • L’associazione con chelanti a minor carico di calcio potrebbe manifestarsi più premiante

  17. EVOLVE™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents) Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  18. EVOLVE Fulfills Criteria of a Well-Designed Outcomes Trial Screening Phase Up to 30 Days Titration Phase (Visits Q2 Wks) Follow up Phase(Visits Q8 Wks) Placebo plus standard of care(n = 1,900) Event-driven study that concludes when approximately 1,882 subjects have experienced a primary composite event Cinacalcet plus standard of care (n = 1,900) • Trial Population • Hemodialysis • iPTH 300 pg/mL • Ca  8.4 mg/dL • Ca x P  45 mg2/dL2 All patients could receive vitamin D sterols and phosphate binders, as necessary, at the discretion of the physician. Day 1 Week 20 Week 52 Enrollment = ~ 1.5 years Follow-up period = ~ 2.5 years Adapted from: Chertow GM, et al. Clin J Am Soc Nephrol. 2007;2:898-905.

  19. EVOLVE: Study Endpoints • Primary Composite Endpoint • Time to: • All cause Mortality or • First nonfatal CV event • Myocardial infarction • Hospitalization for unstable angina • Heart failure • Peripheral vascular event • Secondary Endpoints • Time to: • Individual components of the primary endopoint • Cardiovascular mortality • Stroke • Clinical bone fracture • Parathyroidectomy Adapted from Chertow GM, et al. Clin J Am Soc Nephrol. 2007;2:898-905.

  20. Sample size • The sample size calculation for the primary endpoint assumes a placebo primary composite event rate of approximately 23.2% per year, a 1.5-year enrollment period, a lost to follow up rate of 1% per year, a withdrawal from treatment (dropout) rate of 10% per year in the cinacalcet group, a drop-in rate in the placebo group of 10% per year, and a 10-week lag in the time to achieve the full treatment effect. • Based on a two-sided log-rank test for equality of survivor functions using a 0.044 significance level at the final analysis (which is based on an overall alpha at 0.05 and accounts for 3 planned interim analyses), 1882 subjects must experience a primary composite endpoint to ensure adequate power (90%), with a total sample size of approximately 3800 subjects.

  21. EVOLVE Statistical Analyses Primary Analysis: Unadjusted analysis according to the intention-to-treat principle (ITT) PrespecifiedSecondary Analysis: Multivariate adjustment for baseline characteristics (ITT) • PrespecifiedSensitivity Analysis: • Lag censoring analysis: data censored 6 months after subject stops study drug Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  22. Lag-censoring analysis • Assesses the effect of cinacalcetby censoring (removing) data after patients discontinued study drug • 6 months lag censoring analysis was pre-specified since no further treatment effect was assumed beyond this point • Analyses using lag times of 0, 3, 9, 12, 18 months were also performed Randomization to study Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  23. EVOLVE™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents) Primary EndpointResults Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  24. Primary Composite Endpoint (ITT) not met:Non-significant* 7% Reduction in the Risk of Death or Nonfatal Cardiovascular Events in Patients with SHPT Kaplan-Meier plot of the time to the primary composite endpoint (death, myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event) in EVOLVE™. Placebo 1.0 Cinacalcet 0.9 0.8 0.7 Proportion Event-free 0.6 0.5 Hazard ratio, 0.93 (95% CI, 0.85, 1.02) Log-rank test, P = 0.11* 0.4 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Time (months) Subjects at risk: 1935 1804 1693 1579 1476 1384 1312 1224 1160 1109 1053 996 940 650 404 114 1948 1842 1739 1638 1556 1472 1384 1303 1230 1177 1115 1051 989 679 399 113 * The trial did not meet its primary endpoint in the unadjusted intent-to-treat analysis Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  25. The International Conference on Harmonisation  (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH E9 Guidelines on biostatistical principles in clinical trials' The primary variable (‘target’ variable, primary endpoint) should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objectiveof the trial

  26. EVOLVE: Baseline Patient Demographics Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  27. Primary Composite Endpoint Adjustment for Baseline Characteristics (ITT)*: Nominally Significant** 12% Reduction in the Risk of Death or Nonfatal Cardiovascular Events in Patients with SHPT# * Pre-specified adjustment for up to 40 characteristics, including age (years) at randomisation, BMI (kg/m2),history of CV disease ** Formal statistical significance cannot be claimed, reported P values should be considered nominal # The trial did not meet its primary endpoint in the unadjusted intent-to-treat analysis Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  28. Primary Composite Endpoint Pre-specified 6 Months Lag Censoring Analysis*: Nominally Significant** 15% Reduction in the Risk of Death or nonfatal Cardiovascular Events in Patients with SHPT# Kaplan-Meier plot of the time to the primary composite endpoint (death, myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event) in EVOLVE™. Placebo 1.0 Cinacalcet 0.9 0.8 0.7 Proportion Event-free 0.6 0.5 Hazard ratio, 0.85 (95% CI, 0.76, 0.95) Log-rank test, P = 0.003** 0.4 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Time (months) Subjects at risk: 1935 1789 1615 1299 1080 875 739 625 525 474 419 353 303 180 93 26 1948 1835 1627 1376 1 179 1002 847 731 632 551 491 425 362 239 130 28 * Pre-specified companion analyses with lag censoring, in which data were censored 6 months after patients stopped using a study drug ** Formal statistical significance cannot be claimed, reported P values should be considered nominal # The trial did not meet its primary endpoint in the unadjusted intent-to-treat analysis Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  29. EVOLVE™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents) Secondary endopoints results Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  30. Secondary Endpoints Results (ITT)* * The trial did not meet its primary endpoint in the unadjusted intent-to-treat analysis ** Formal statistical significance cannot be claimed, reported P values should be considered nominal HR = hazard ratio; CI = confidence interval. Elaborated from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  31. Secondary Endpoints (ITT): Nominally Significant* Reduction in the Risk of Parathyroidectomy (56%) and Severe Unremitting HPT (57%) in Patients with SHPT 1.0 Severe unremitting HPT: plasma PTH >1000 pg/mL (106.0 pmol/L) with serum calcium >10.5 mg/dL(2.6 mmol/L) on two consecutive occasions; or plasma PTH >1000 pg/mL (106.0 pmol/L) and serum calcium >10.5 mg/L (2.6 mmol/L) on one occasion with prescription of commercial cinacalcet within 2 months, or surgical parathyroidectomy 0.9 0.8 Time To First Parathyroidectomy 0.7 Proportion Event-free 0.6 Placebo 0.5 Cinacalcet Hazard ratio, 0.44 (95% CI, 0.36, 0.54) 0.4 Log-rank test, P < 0.001* 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 1.0 0.9 0.8 0.7 Time to First Episode of Severe Unremitting HPT Proportion Event-free 0.6 0.5 Hazard ratio, 0.43 (95% CI, 0.37, 0.50) 0.4 Log-rank test, P < 0.001* 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Time (months) * Since the primary end point of the study was not significant, reported P values should be considered nominal Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  32. The discontinuation of the studydrug wasparticularly high Power 90%  54%

  33. EVOLVE™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents) Biochemical results Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  34. EVOLVE: Biochemical Parameters during the study (ITT)Substantial Reductions in PTH and Ca Levels in Patients with SHPT* 10.9 Placebo 1800 8.0 74 Median iPTH Median  Serum Calcium Cinacalcet 10.6 70 1600 7.5 66 10.3 1400 7.0 62 10.0 1200 6.5 58 • iPTH (pg/mL) 9.7 • Ca (mg/dL) 1000 6.0 • Ca x P (mg2 x dL2) 54 • P (mg/dL) 9.4 800 5.5 50 9.1 600 5.0 46 8.8 400 4.5 42 8.5 200 4.0 38 8.2 3.5 0 34 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 0 0 4 4 8 8 12 12 16 16 20 20 24 24 28 28 32 32 36 36 40 40 44 44 48 48 52 52 56 56 60 60 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Median Serum Phosphorus Median  Ca x P Product Time (months) Time (months) Time (months) Time (months) * The trial did not meet its primary endpoint in the unadjusted intent-to-treat analysis iPTH = intact parathyroid hormone; P = phosphorus; Ca = calcium; Ca x P = calcium phosphorus product. Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  35. Concomitant medications over time in cinacalcet-treated and placebo-treated patients while receiving study drug. Proportion (SE) of patients receiving vitamin D sterols (panel A), mean (SE) weekly intravenous paricalcitol-equivalent dose(panel B), proportion (SE) of patients receiving phosphate binder (panel C), and proportion (SE) of patients receiving calcium-containing phosphate binder (panel D) IV Paricalcitol-equivalent dose is calculated using the following: 2 mcgParicalcitol(IV) = 1 mcgDoxercalciferol(IV) = 1 mcgAlfacalcidol (IV) = 0.5 mcgCalcitriol (IV) = 1 mcgParicalcitol (PO) = 0.5 mcgAlfacalcidol (PO) = 0.25 mcgCalcitriol (PO)

  36. EVOLVE™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents) Safety results Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  37. EVOLVE: Adverse Events Exposure Adjusted Rates were calculated as the median duration of study-drug exposure was longer in the cinacalcet group than in the placebo group (21.2 months vs. 17.5 months) *P < 0.001; †P < 0.05; ‡P < 0.01 EAR: Exposure Adjusted Rates Adapted from Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624

  38. Increased Cardio-vascular Mortality Coronaric &Vascular calcifications SHPT & Ca/Pi/VitD assoc. Changes PTX Muscle-skeletalpain Bonedeformities Bonefractures Bone Disease

  39. The average rate of PTX beforecinacalcet approval was 11.4 /1000 py and was 3.6 /1000 pyaftercinacalcetreimbursement Lafrance JP et al BMC Nephrol2013

  40. Messaggi conclusivi • Il mancato controllo biochimico dei parametri del MM è associato ad una progressione dell’IPS verso forme non controllate di IPS, con conseguenti gravi alterazioni ossee • Queste forme portano all’indicazione di una PTX • L’efficacia della terapia sul controllo dell’IPS è prevalentemente basata sulla sua efficacia del controllo dei parametri biochimici • La carenza d’informazione riguarda: • Gli step decisionali nell’uso dei nuovi farmaci • La tollerabilità e la sicurezza nell’uso di questi farmaci • Il profilo di costo-efficacia

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