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“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

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

Piergiorgio Messa

Nephrology, Dialysis and RenalTransplant

Milano-Italy


SHPT chiarezza

&

Ca/Pi/VitD

assoc. Changes

Muscle-skeletalpain

Bonedeformities

Bonefractures

Bone Disease


….. chiarezza uncontrolled SHP leadsto

extremely severe bonedisease


Increased chiarezza

Cardio-vascular

Mortality

Coronaric &Vascular

calcifications

SHPT

&

Ca/Pi/VitD

assoc. Changes

PTX

Muscle-skeletalpain

Bonedeformities

Bonefractures

Bone Disease


Therapy chiarezza failure in

controlling SHP

Ca & Pi

Undesiredeffects

oftherapy

(vitD/Ca salts)


Medical intervention chiarezza

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


Study hypothesis

ADVANCE STUDY chiarezza

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)


ADVANCE STUDY chiarezza

Floege J et al NDT 2010


Study endpoints
Study Endpoints chiarezza

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


Baseline Laboratory Parameters chiarezza

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.


Percent Change chiarezza 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.


Median Treatment Differences, All Sites chiarezza

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.


Weekly Active Vitamin D Dose (IV chiarezza 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.


Mean (SE) Daily Calcium-Containing Phosphate Binder Dose by Treatment Group

Raggi P et al NDT 2012


Limiti
limiti Treatment Group

  • 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


Suggerimenti
Suggerimenti Treatment Group

  • 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


Evolve ev aluation o f cinacalcet hcl therapy to l ower cardio v ascular e vents

EVOLVE Treatment Group™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents)

Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624


Evolve fulfills criteria of a well designed outcomes trial
EVOLVE Fulfills Criteria of a Well-Designed Outcomes Trial Treatment Group

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.


Evolve study endpoints
EVOLVE: Study Endpoints Treatment Group

  • 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.


Sample size
Sample Treatment Groupsize

  • 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.


Evolve statistical analyses
EVOLVE Statistical Analyses Treatment Group

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


Lag censoring analysis
Lag-censoring analysis Treatment Group

  • 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


Evolve ev aluation o f cinacalcet hcl therapy to l ower cardio v ascular e vents1

EVOLVE Treatment Group™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents)

Primary EndpointResults

Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624


Primary Composite Endpoint Treatment Group(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


The  Treatment GroupInternational 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


Evolve baseline patient demographics
EVOLVE: Baseline Patient Demographics Treatment Group

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


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


Primary Composite Endpoint Pre-specified 6 Months Characteristics (ITT)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


Evolve ev aluation o f cinacalcet hcl therapy to l ower cardio v ascular e vents2

EVOLVE Characteristics (ITT)™ (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


Secondary endpoints results itt
Secondary Endpoints Results (ITT)* Characteristics (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


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


The in the Risk of discontinuation

of the studydrug

wasparticularly high

Power

90%  54%


Evolve ev aluation o f cinacalcet hcl therapy to l ower cardio v ascular e vents3

EVOLVE in the Risk of ™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents)

Biochemical results

Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624


EVOLVE: in the Risk of 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


Concomitant medications over time in in the Risk of 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)


Evolve ev aluation o f cinacalcet hcl therapy to l ower cardio v ascular e vents4

EVOLVE in the Risk of ™ (EValuationOf CinacalcetHCl Therapy to Lower CardioVascularEvents)

Safety results

Chertow GM, et al. N Engl J Med. Epub 2012 Nov 3; DOI: 10.1056/NEJMoa1205624


Evolve adverse events
EVOLVE: Adverse Events in the Risk of

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


Increased in the Risk of

Cardio-vascular

Mortality

Coronaric &Vascular

calcifications

SHPT

&

Ca/Pi/VitD

assoc. Changes

PTX

Muscle-skeletalpain

Bonedeformities

Bonefractures

Bone Disease


The in the Risk of average rate of PTX beforecinacalcet approval was 11.4 /1000 py and was 3.6 /1000 pyaftercinacalcetreimbursement

Lafrance JP et al BMC Nephrol2013


Messaggi conclusivi
Messaggi conclusivi in the Risk of

  • 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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