clinical perspectives from recent ckd trials...2017/02/14 · clinical perspectives from recent ckd...

Dick de Zeeuw Department of Clinical Pharmacy and Pharmacology

University Medical Center Groningen

The Netherlands

Clinical Perspectives from Recent CKD Trials Failure of hard outcome renal CKD progression trials

New avenues?

Disclosure: Consultant to AbbVie, Astellas, AstraZeneca, Chemocentryx, Fresenius,

Hemocue, Janssen, Novartis, Pfizer, Reata, Takeda; honoraria paid to Institution

Recent failed trials in CKD protection

•  Recently failed CKD progression trials: §  ON-TARGET (dual RAAS) §  SUN (sulodexide) §  TREAT (EPO; darbepoetin) §  ALTITUDE (dual RAAS; DRI) §  VA-NEPHRON-D (dual RAAS) §  BEACON (inflammation; bardoxolone) §  ASCEND (endothelin antagonist; avosentan)

Dick de Zeeuw June 2014

Reason for trial failure

•  the new therapies are developed on the assumption that the intervention is providing additive renal (CV) protection

•  Indeed, many of the failed trials conclude that the investigational drug was failing because of the characteristics of the drug itself or because of the wrong target/surrogate

I submit the hypothesis that it is not the wrong drug

but the wrong trial design that might explain the trial failures


Trial failure; design issues?


•  Design issues: §  Too low-risk population §  No effect on surrogate §  Too high dose §  Wrong endpoints §  Too many side effects


ONTARGET: CV and renal outcome during ACEi (ramipril) vs ACEi (ramipril) + AIIA (telmisartan) in high-risk patients

Yusuf S, et al. N Engl J Med 2008;358:1547–9 Mann J, et al. Lancet 2008;372:547–53

0.005

0.004

0.003

0.002

0.001

0 0 1 2 4

Years to follow-up

Cum

ulat

ive

dial

ysis

inci

denc

e

3 5

Telmisartan + Ramipril Ramipril

Telmisartan

Cum

ulat

ive

CV

out

com

e in

cide

nce

0.0 0.05 0.10 0.15 0.20 0.25

0 1 2 3 4

Ramipril Telmisartan + Ramipril

R 8576 8214 7832 7473 7095 T&R 8502 8134 7740 7377 7023


ONTARGET; Baseline albuminuria

•  Microalbuminuria was present in 13.1% of all participants §  29.7% of those with diabetes §  9.2% of those without known diabetes

•  Macroalbuminuria was seen in 4.0% of all participants §  12.2% of those with diabetes §  1.4% of those without known diabetes.

Mann JF et al; New Engl J Med 2008 Dick de Zeeuw June 2014

ONTARGET: Incidence of primary and secondary renal outcomes and of its components

Ramipril N

Telmisartan N

Ramipril + telmisartan

N

Telmisartan Vs Ramipril

HR p

Ram +Telm Vs ramipril

HR

p

All dialysis, doubling, death

1150 1147 1233 1·00 0·968 1·09 0·037 All dialysis and doubling

174 189 212 1·09 0·420 1·24 0·038

All dialysis 48 51 63 1·07 0·747 1·33 0·133

All death 1014 989 1065 0·98 0·641 1·07 0·144

Doubling 140 155 166 1·11 0·378 1·20 0·110 Acute dialysis 13 20 28 1·55 0·221 2·19 0·020 Chronic dialysis 33 31 34 0·94 0·817 1·05 0·854

Mann JF et al; New Engl J Med 2008 Dick de Zeeuw June 2014

ONTARGET: Effect of treatment on serum potassium

Time (years) R - 1 R W6 2 Study

End

Seru

m p

otas

sium

(mm

ol/L

)

4.30 4.35 4.40 4.45 4.50 4.55 4.60

Dual therapy

Mono therapy

Lambers Heerspink et al; EJPC 2014 Dick de Zeeuw June 2014

ONTARGET: Relationship on-treatment serum potassium and cardiovascular outcome

3 4 5 6 7 Serum potassium at Week 6

0

0.5

1

1.5

2

2.5

0

5

10

15

20

25 H

azar

d R

atio

CV

Out

com

e

Patie

nts

%

Adjusted risk: Age, gender, diabetes, eGFR, UACR, systolic blood pressure, diuretics


ONTARGET: Relation week-6 serum potassium and renal outcome

Serum potassium at Week 6 3 4 5 6 7

0

0.5

1

1.5

2

2.5

3

3.5

4

0

5

10

15

20

25

30

35

40 H

azar

d R

atio

Ren

al O

utco

me

Patie

nts

%

Adjusted risk: Age, gender, diabetes, eGFR, UACR, systolic blood pressure, diuretics




•  Design issues: §  Too low-risk population YES; eGFR >70; Macroalb 4% §  No effect on surrogate §  Too high dose §  Wrong endpoints YES; Acute dialysis §  Too many side effects YES; Potassium increase


SUN-Overt; effect of Sulodexide on renal outcome in type 2 diabetes with nephropathy

Packham D, et al. J Am Soc Nephrol 2012;23:123–30

1.00

0 3 6 9 12 15 18 21 24 27 30 Time (months after randomization)

0.00

0.25

0.50

0.75

Pro

babi

lity

of n

o re

nal e

ndpo

int

Placebo

Sulodexide

Number of participants still at risk (number of endpoints)

Placebo 580 (8) 396 (5) 243 (10) 101 (7) 6

Sulodexide 549 (0) 403 (9) 242 (9) 105 (8) 6


SUN-Micro; effect of Sulodexide on albuminuria in type 2 diabetes with microalbuminuria

Lewis et al AJKD 2011 Dick de Zeeuw June 2014



•  Design issues: §  Too low-risk population §  No effect on surrogate YES §  Too high dose §  Wrong endpoints §  Too many side effects


TREAT; CV (Death, MI, Myocardial Ischemia, HF, Stroke) and Renal (Death or ESRD) Composite

Pfeffer M, et al. N Engl J Med 2009;361:2019–32

0

10

20

30

40

50

0 6 12 18 24 30 36 42 48

Pat

ient

s w

ith C

V e

vent

s (%

)

HR: 1.05 (0.94–1.17) p=0.41

Darbepoetin alfa 632 (31.4%)

Placebo 602 (29.7%)

0

10

20

30

40

50

0 6 12 18 24 30 36 42 48

Pat

ient

s w

ith re

nal e

vent

s (%

)

Months

HR: 1.06 (0.95–1.19) p=0.29

Darbepoetin alfa 652 (32.4%)

Placebo 618 (30.5%)

Months


TREAT; post-hoc analysis; difference in CV outcome (Death, MI, Stroke, HF) for Hb non-responders vs responders

0.00

0.10

0.20

0.30

0.40

Frac

tion

of p

atie

nts

1889 1611 1138 514 117 Placebo 1401 1234 854 408 94 471 394 272 125 30

Number at risk 0 1 2 3 4

Hyporesponsive

Placebo arm

0.50

1889 1611 1138 514 117 1401 1234 854 408 94 Responsive 471 394 272 125 30 Hyporesponsive

0 1 2 3 4

1401 1234 854 408 1401 1234 854 408 94 471 394 272 125 30

0 1 2 3 4 Years

Responsive

Solomon S, et al. N Engl J Med 2010;363:1146–55 Dick de Zeeuw June 2014



•  Design issues: §  Too low-risk population §  No effect on surrogate YES (with high dosing) §  Too high dose YES §  Wrong endpoints §  Too many side effects ?


ALTITUDE: CV and renal secondary composite endpoint

Parving H, et al. N Engl J Med 2012;367:2204–13

Car

diov

ascu

lar

com

posi

te o

utco

me

(%)

0

10

20

30

40

0 6 12 18 24 30 36 42 48

Months since randomization No. at risk

Aliskiren: Placebo:

4274 4287

4094 4117

3939 3944

3726 3741

3019 3079

2340 2385

1382 1427

679 680

85 86

Hazard ratio, 1.11 (95% CI, 0.99–1.25); p=0.09

Aliskiren

Placebo

Ren

al

com

posi

te o

utco

me

(%)

Aliskiren

Placebo

0

10

20

30

40

0 6 12 18 24 30 36 42 48

Months since randomization No. at risk

Aliskiren: Placebo:

4274 4287

4168 4185

4042 4058

3846 3874

3119 3161

2409 2428

1417 1443

705 693

96 91

Hazard ratio, 1.03 (95% CI, 0.87–1.23); p=0.74


ALTITUDE; more blood pressure and albuminuria lowering during Aliskiren

Parving et al; NEJM 2012

Time Period (months)

0.6

0.8

1.0

1.2

0 6 12 18 24 30 36 42

Rat

io o

f geo

met

ric m

eans

of

urin

ary

albu

min

:cre

atin

ine

ratio

UACR

Aliskiren

Δ 14% Δ 1.3

Sys

tolic

/Dia

stol

ic B

P (m

mH

g)

Time Period (months)

0 6 12 18 24 30 36 42

73

75

138

140

142

144

136

BP

Aliskiren

Δ 0.6

Placebo Placebo


Relationship between short-term decrease in albuminuria and long-term renal risk reduction:

different randomized clinical trials in different populations

Lambers Heerspink H, De Zeeuw D. Nephron Clin Pract 2010;116:c137–42

0 10 20 30 40 50

1.5

1.2

1.0

0.5

0.3

Albuminuria reduction (%)

Haz

ard

ratio

ES

RD

AVOID ALTITUDE


ALTITUDE; effect of Aliskiren on serum potassium course

Parving H, et al. N Engl J Med 2012;367:2204–13

Time period (months)

4.45

4.50

4.55

4.60

4.65

4.70

0 6 12 18 24 30 36 42

Ser

um p

otas

sium

(mm

ol/L

) Aliskiren




•  Design issues: §  Too low-risk population §  No effect on surrogate YES §  Too high dose §  Wrong endpoints §  Too many side effects YES


VA-NEPHRON-D: ACEi + ARB no renal protection in diabetes with nephropathy (n=1148)

Fried L, et al. N Engl J Med 2013;369:1892–903

Number at risk

Losartan + placebo 724 641 543 453 335 238 149 75 14

Losartan + lisinopril 724 631 534 457 347 245 139 69 10

Percentage of patients (95% CI)

5.7 (4.1–7.8) 18.7 (15.6–22.3) 30.4 (26.1–35.3) 42.4 (34.8–50.8) Losartan + placebo

5.3 (3.8–7.3) 15.2 (12.3–18.6) 28.2 (23.8–33.4) 48.3 (35.4–63.0) Losartan + lisinopril

0 10 20 30 40 50 60 70 80 90

100

Prim

ary

endp

oint

(% o

f pat

ient

s)

0 6 12 18 24 30 36 42 48 54 Months since randomization

Losartan + placebo

Losartan + lisinopril

p=0.30

Primary endpoint


VA-NEPHRON-D: Acute Kidney Injury


Number at risk



5.2 (3.8–7.2) 11.2 (8.8–14.1) 15.4 (12.4–19.1) 18.3 (14.2–23.3) Losartan + placebo

9.2 (7.3–11.7) 16.6 (13.8–20.0) 23.7 (20.0–28.0) 40.8 (28.2–56.4) Losartan + lisinopril


Months since randomization

0 10 20 30 40 50 60 70 80 90

100

Acu

te k

idne

y in

jury

(% o

f pat

ient

s)

0 6 12 18 24 30 36 42 48 54

Losartan + placebo

Losartan + lisinopril p<0.001

Acute Kidney Injury


VA-NEPHRON-D: Hyperkalemia


Number at risk



2.4 (1.5–3.9) 4.0 (2.7–5.9) 5.1 (3.4–7.5) Losartan + placebo

6.5 (4.8–8.6) 9.9 (7.8–12.7) 13.4 (10.4–17.0) Losartan + lisinopril


Months since randomization

0 10 20 30 40 50 60 70 80 90

100

Hyp

erka

lem

ia (%

of p

atie

nts)

0 6 12 18 24 30 36 42 48 54

Losartan + placebo Losartan + lisinopril

p<0.001

Hyperkalemia




•  Design issues: §  Too low-risk population §  No effect on surrogate §  Too high dose §  Wrong endpoints YES §  Too many side effects YES


BEACON; Primary outcome (ESRD or CV death) and Secondary outcome (heart failure)

BARD ── 1088 1077 1050 982 904 756 571 429 297 137 16 0

PBO ── 1097 1095 1076 1004 922 768 596 439 318 142 19 0

0.00

0.05

0.10

0.15

0.20

0.25

0 4 8 12 16 24 32 40 48 56 64 72

Est

imat

ed p

ropo

rtion

of p

atie

nts

with

E

SR

D o

r CV

dea

th b

y S

DT2

< 20% of patients

Weeks since randomization Weeks since randomization

1088 1045 1006 942 864 723 548 417 288 133 15 0 1097 1089 1070 994 907 762 591 436 315 135 20 0

BARD PBO

< 20% of patients

Est

imat

ed p

ropo

rtion

of p

atie

nts

hosp

italiz

ed fo

r/ di

ed o

f HF

by S

DT

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0 4 8 12 16 24 32 40 48 56 64 72

De Zeeuw et al; NEJM 2013 Dick de Zeeuw June 2014



•  Design issues: §  Too low-risk population §  No effect on surrogate §  Too high dose ? §  Wrong endpoints §  Too many side effects YES


ASCEND; Effect of endothelin-antagonist Avosentan on primary renal outcome (doubling of serum creatinine, ESRD or death) in

patients with type 2 diabetes and nephropathy (n = 1392)

Mann J, et al. J Am Soc Nephrol 2010;21:527–35

ASCEND; cumulative incidence of CHF by avosentan and placebo treatment arm

Hoekman et al; CJASN 2014; 9: 490-498

Number at risk Avosentan 25 455 274 201 162 Avosentan 50 478 289 207 159 Placebo 459 347 263 207

0 2 4 6

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14 P

ropo

rtion

of p

atie

nts

with

CH

F

Months of follow-up

Avosentan 25

Avosentan 50 Placebo




•  Design issues: §  Too low-risk population §  No effect on surrogate §  Too high dose YES §  Wrong endpoints §  Too many side effects YES



•  Design issues:

§  Too low risk population Enrichment for risk

§  No effect on surrogate Select responders

§  Too high dose Dose to optimal effect

§  Wrong Endpoints Correct endpoint definition

§  Too much side effects Select “good” responders

What would have happened if previous trials would have looked at:

§  The responders

§  the good responders Dick de Zeeuw June 2014

ONTARGET/TRANSCEND; Post hoc; Changes in albuminuria predict outcome in vascular disease or high risk diabetes

Schmieder et al; JASN 2011

0,4 0,8 1,2 1,6

Hazard Ratio 0,6 1.0 1,4 1,8

0.026

0.140

0.032

0.019

0.005

<0.0001

<0.0001

<0.0001

All cause mortality

Decrease > 50% vs minor change

minor change

Increase > 100% vs minor change

CV Death Decrease > 50% vs minor change

minor change


Combined CV Endpoint


minor change


Combined Renal Endpoint


minor change


Decrease > %0% Increase > 100%


ONTARGET/TRANSCEND; Post hoc; Changes in albuminuria is best(?) predictor of outcome in patients with vascular disease or

high risk diabetes

Schmieder et al; Diabetologia 2014

ALTITUDE; Post hoc; Adjusted renal/CV hazard by 6 month albuminuria change (8561 type 2 diabetes with CKD and/or CV

disease)

Adjusted for the baseline covariates including age, gender, log-transformed UACR, eGFR, systolic blood pressure, diastolic blood pressure, HemoglobinA1c, body mass index, HDL cholesterol, LDL-cholesterol, log-transformed triglycerides, hemoglobin, history of cardiovascular disease, serum potassium current smoking, current drinking and randomized active treatment, and the change of covariates for 6 months including eGFR, systolic blood pressure, diastolic blood pressure and serum potassium

0.2

0.4

0.6

0.8 1.0 1.2 1.4 1.6

Haz

ard

ratio

(95%

CI)

Renal events

0.2

0.4

0.6

0.8 1.0 1.2 1.4 1.6

Cardiovascular events

p for trend <0.001 p for trend <0.001

N=2738

N=1548

N=1251

N=2514

N=2738

UACR change

N=1548

N=1251

N=2514

<-30 -30-<0 0-30 >30% <-30 -30-<0 0-30 >30%

UACR change

Lambers Heerspink et al. ASN 2013 Dick de Zeeuw June 2014

BEACON; Post hoc analysis; Endpoints after excluding patients with BNP>200 pg/ml

All Patients BNP ≤ 200, No Prior HF Hospitalization

Treatment PBO (n = 1097)

BARD (n = 1088)

PBO (n = 544)

BARD (n = 503)

Event Primary Composite 69 (6) 69 (6) 25 (5) 15 (3) ESRD 51 (5) 43 (4) 20 (4) 8 (2) Any Cardiovascular Death 19 (2) 27 (2) 6 (1) 7 (1) Secondary Composite 86 (8) 139 (13) 23 (4) 27 (5) Heart Failure 55 (5) 96 (9) 10 (2) 12 (2) Fatal or Non-fatal Myocardial Infarction 16 (1) 19 (2) 6 (1) 6 (1) Fatal or Non-fatal Stroke 11 (1) 14 (1) 5 (1) 2 (<1) All-Cause Death 31 (3) 44 (4) 8 (1) 11 (2) Skin and subcutaneous tissue disorders 1 (<1) 4 (<1) 0 (<1) 3 (1) Surgical and medical procedures 0 2 (<1) 0 (0) 1 (0) Vascular disorders 18 (2) 20 (2) 10 (2) 8 (2)

Chin et al; submitted Dick de Zeeuw June 2014

From trial to practice

•  We are carrying out hard end point trials for registration reasons: §  The trials require to be representative of the patients to be treated

with that indication in real life practice

•  In trial design: §  Usually fixed dose §  If no effect, drug is continued and patient stays in trial §  Side effects are part of outcome of trial

•  In real life drug treatment: §  Dose is titrated to a target §  If no effect, drug is stopped §  If side effect:

–  Side effect is managed –  if side effect persists, drug is stopped


Future

•  Do a trial in which we: §  Enrich for risk §  Enrich for good response §  Enrich to take out bad response


Screening

Period

(up to 14 days)

Placebo QD

Double-Blind Treatment Period

Atrasentan 0.75 mg QD

Run-in Period

2 weeks if receiving MTLD of

RAS inhibitor

Run-in Period 4–12 weeks if not receiving max

tolerated labeled dose of RAS inhibitor

6-week

Enrichment Period

Atrasentan 0.75 mg

QD

Follow-up Period

(45 days)

>30% UACR

reduction

Atrasentan 0.75 mg QD

Placebo QD

<30% UACR

reduction

n=3148

n=1000

51%

Primary endpoint Time to first occurrence of composite renal endpoint: doubling of serum creatinine or onset of ESRD (needing chronic dialysis or renal transplantation or renal death)

Study completion 425 distinct primary renal events have occurred (adjudicated) in the responder population

De Zeeuw D, et al. Manuscript in preparation; ClinicalTrials.gov NCT01858532

SONAR; Protocol scheme


CONCLUSIONS

•  Treatment of CKD progression (particularly in diabetes) leaves a large proportion of residual risk

•  Recent efforts to slow progression with new medications on top of single RAASi have been unsuccessful

•  These failures appear to be largely due to design failures


clinical perspectives from recent ckd trials...2017/02/14 · clinical perspectives from recent ckd...

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