maxime dougados paris-descartes university, medicine faculty; upres ea-4058; ap-hp, cochin hospital,...

Maxime DOUGADOSParis-Descartes University, Medicine Faculty; UPRES EA-4058;

AP-HP, Cochin Hospital, Rheumatology B DptPARIS, France

Status versus Changes:

Feeling Good versus Feeling Better

Status versus Changes: Feeling Good versus Feeling Better

0

10

20

30

40

50

60

70

80

90

100

-1 0 1 2 3 4 5 6

Placebo

0

10

20

30

40

50

60

70

80

90

100

-1 0 1 2 3 4 5 6

Placebo

0

10

20

30

40

50

60

70

80

90

100

-1 0 1 2 3 4 5 6

Placebo

Variable PAIN (VAS 0-100)P

ain

Patient #1

Placebo

Placebo Placebo Placebo Placebo Placebo Placebo

0

10

20

30

40

50

60

70

80

90

100

-1 0 1 2 3 4 5 6

Placebo0 1 2 3 4 5 6 months

(60)

30

Pai

n

Patient #2

0 1 2 3 4 5 6 months

(60)

30

Pai

n

Patient #3

0 1 2 3 4 5 6 months

(60)

30

Pai

n

Patient #4

0 1 2 3 4 5 6 months

(60)

30

100

0

100

0

100

0

100

0

=50 =50

=50 =50


Points to consider

a) How to present the results

b) How to switch a continuous variable into a dichotomous variable?

c) How to evaluate the clinical relevance of the technic of reporting?


Responder: change in VAS (0-100) during the study >MCII (Minimum Clinically Important Improvement)

Remission/satisfied: absolute value of VAS (0-100) at the end of the study <PASS (Patient Acceptable Symptom State)

0 1 2 3

0

20

40

60

80

100

Placebo Active

0

20

40

60

80

100

Placebo Active

Continuous variablemean change

Binary variable(changes)

Binary variable(status)

weeks

Pai

n (

0-1

00 m

m V

AS

)

% r

e sp

on

de r

s *

% s

a ti s

fied

/ re

mis

s io

n**

Placebo

Active

How to present the results


Technics of reporting

Mean changes versus percentage patients

It’s good to feel better but it’s better to feel good

It’s better to feel better/good AS SOON AS POSSIBLE

It’s even better to feel better/good as soon as possible and FOR AS LONG AS POSSIBLE

It’s good to feel better/good for as long as possible

Percentage patients


Presentation of continuous variables Table (example: NSAID in painful shoulder*)

Figure (example: TICORA trial**)

*Dougados M et al. Plos Clin trials2007,2(3),e9**Grigor C et al. Lancet, 2004;364:263-9

6.9

3.5

Treatment group Baseline Changes

Active 68 14 -38 26

Placebo 68 14 -27 25

0

1

2

3

4

5

6

0 3 6 9 12 15 18

Group A = "routine"Group B = "DAS"

DA

S

Groupe A = traitement selon les habitudes du rhumatologue (« pratique quotidienne »)

Groupe B = traitement selon les résultats du DAS (« pratique guidée »)


Presentation of dichotomous variables

65

22

0

20

40

60

80

100

Placebo Rituximab

2 150

20

40

60

80

100

Placebo Rituximab

To feel better To feel good

EU

LA

R r

esp

on

der

s %

pat

i en

ts*

DA

S <

3. 2

%

pat

i en

ts

*Cohen SB et al. Arthritis Rheum 2006;2793-806

It’s good to feel better but it’s better to feel good (example: Rituximab versus placebo in RA: REFLECT study)


Presentation of dichotomous variablesIt’s better to feel better/good as soon as possible

(example: TEMPO trial).

Copyright ©2006 BMJ Publishing Group Ltd.

van der Heijde, D et al. Ann Rheum Dis 2006;65:328-34

Figure 3 Kaplan-Meier estimation of time to HAQ disability scores & lt; =0.5 and sustained for 6 months.



It’s even better to feel better/good as soon as possible for AS LONG AS POSSIBLE (example: NSAIDs versus placebo in acute shoulder pain).

Dougados M et al. Plos Clin trials2007,2(3),e9

0

20

40

60

80

100

-1 0 1 2 3 4 5 6 7

Placebo

Active

Su

cc

es

s*

* % patients with a pain VAS <30 over time

p=0.0027

0

20

40

60

80

100

-1 0 1 2 3 4 5 6 7

Placebo

Active

Su

cc

es

s*

* % patients with a sustained pain VAS <30

p=0.0036



It’s good to feel better/good for AS LONG AS POSSIBLE.

% patients with a « success » during 2 or 3 consecutive visits.

% patients with a « success » during 6 consecutive monthly visits in a one/two years trial.

ConRew Scores


Presentation of continuous variables

0

10

20

30

40

50

60

70

80

-1 1 3 5 7 9 11Placebo

Patient #x

0 1 2 3 4 5 6 7 8 9 10 11 12 months

100

0

30

Evaluation of patient #xMajor Clinical Response (FDA proposal)MCR = yes if success at 6 consecutive visits

x x x x x x x = YESCon Rew System

Unweighted 0 I I 0 I I I I I I I 0 I = I0

Weighted 1 0 I I+I 0 I+I I+I I+I I+I I+I I+I I+I 0 I = I7

Weighted 2 0 I I+I 0 I I+I I+2 I+3 I+4 I+5 I+6 0 I = 32


1.71.9

4.4

0

5

0 1 2 3 4

23.8

9.95.7

0

50

MTX ETN ETN + MTX

AC

R2

0- M

CR

(% p

ati

en

t s)

It’s good to feel good/better for as long as possible(example: TEMPO trial*)

Co

n R

ew

Un

we

i gh

t ed

(% p

ati

etn

s)

Co

n R

ew

We

i gh

ted

1.01.1

2.4

0

5

0 1 2 3 4MTXn = 228

ETNn = 223

ETN + MTXn = 231

MTXn = 228

ETNn = 223

ETN + MTXn = 231n = 228 n = 223 n = 231

*van der Heijde D et.al. Ann Rheum Dis 2006;64:1582-7


Points to consider





How to switch a continuous into a dichotomous variable?

Doctor’s perspective

Patient’s perspective

Trialist’s perspective




Objective: to propose a cut-off which takes into accountthe variability of the technic.

Methods: Bland & Altman (Smallest Detectable Difference)


Smallest Detectable Difference (SDD) orMinimal Individual Difference (MID)*

Patient1....

30

*Bland & Altman, Lancet 1986;i:307-10.

Analysis 1a1

.

.

.

.x1

Analysis 2a2

.

.

.

.x2

Delta(a1 -a2)

m(x1-x2) ± SD (x1-x2)




-2

-1,5

-1

-0,50

0,5

1

1,5

2

0 1 2 3 4 5 6

Mean-2SD

Mean+2SD

Mean

Mean JSW (mm)

Smallest Detectable Difference

Example: Radiological hip joint space width

*Auleley GR…Dougados M, Ann Rheum Dis, 2000;59:422-7






Objective: to propose a cut-off which takes into accountthe capacity to predict a « hard » end-point.

Methods: - Longitudinal study- R.O.C. technic


Example: Radiological hip joint space width (mm)*

Study design:

X-rays:

Requirement to THR:

N = 384ROC curve analysis

/ / / / / / / / / / / / / / / / /

Years 0 2 5

Years 0 2 5

*Maillefert JF, …, Dougados M. Rheumatology (Oxford) 2002;41:142-7


Doctor’s perspective(Predictive validity)


0 m m- 0 . 1 m m- 0 . 2 m m- 0 . 3 m m- 0 . 4 m m

- 0 . 5 m m

- 0 . 6 m m

- 0 . 7 m m- 0 . 8 m m- 1 m m

- 1 . 1 m m

- 1 . 3 m m

706050403020100

100

80

60

40

20

0

Doctor’s perspective (Predictive validity)Example: Radiological hip joint space width (mm)*

Se = % patients with a change in JSW (mm) over a specific cut-off between baseline and year 2 requiring a Total Hip Replacement between year 2 and year 5.

1-Spe = % patients with a change in JSW (mm) below a specific cut-off between baseline and year 2 not requiring a Total Hip Replacement between year 2 and year 5.

Ab

solu

te c

han

ges

in

JS

W b

etw

een

b

asel

ine

and

2 y

ear

foll

ow

-up

Sensitivity (%)

1- specificity




Pat

i en

ts w

i th

ou

t T

HA

(%

)

Time from baseline (months

Decrease in JSW ≤ 0.4 mm

Decrease in JSW > 0.4 mm

Example: Radiological hip joint space width (mm)*

Patients with a radiological JSW change over 0.4 mm between baseline and year 2 (n = 171).

Patients with a radiological JSW change below 0.4 mm between baseline and year 2 (n = 213).

6050403020100

100

90

80

70

60

50

40

30

20

1

How to switch a continuous into a dichotomous variable?Doctor’s perspective (Predictive validity)



Number ofpatients

X-rays (Change in joint space width: mm)

N = 423

0

40

80

120

160

200

240

+0,4 0,0 -0,4 -0,8 -1,0 -1,4 -1,8 -3,0

How to switch a continuous into a dichotomous variable?Example: change in JSW in hip OA


% patients

RadiologicalprogressionYES

n = 90NO

n = 333

0

20

40

60

80

100


Example: change in JSW in hip OA




Objective: to propose a cut-off which takes into accountthe patient’s opinion.

Methods: • Study design• Cross-sectional (PASS)• Longitudinal (MCII)

• Technic• R.O.C.• 75th percentile


Determination of the optimal cut-offs in changes in changes (MCII) and/or absolute values (PASS) in symptomatic OA variables


4 weeks duration

Baseline – final visits

At baseline and final visits, outcome measures

At final visit, « gold standard » questions

Pain Function Global

Improvement Status

MCII - PASS



Aspects of the cumulative distribution function used to determine the PASS (pain scores in patietns with knee OA)


*Tubach F, …, Dougados M et al. Ann Rheum Dis 2005;64:28-33,34-7

Low rate Intermediate tertile High tertile

Pai

n V

AS

How to evaluate the clinical relevance of the technic of reporting?Responder versus Status: the patient’s perspective




Low rate Intermediate tertile High tertile

Pai

n V

AS

Baseline value – MCII = PASS




MCII

PASS

Baseline absolute value


Points to consider





How to evaluate the clinical relevance of the technic of reporting?

The doctor’s perspective

The patient’s perspective

The trialist’s perspective



Objective: To decrease the number of patients to be recruited in a trial.

Methods: Sample size calculation based on the proposed technic of reporting




= 5%, = 10%, two tailed test

Expected placebo effect: the one observed in a previous trial with the proposed technic of reporting.

Expected active effect: the one observed in a previous trial with the proposed technic of reporting.

The trialist’s perspective(Number Need to Study)

The lowest NNS, the highest value of the technic.


How to evaluate the clinical relevance of the technic of reporting? The trialist’s perspective

(NNS: Number Need to Study)(example: AIM trial*)

*Dougados M et al., Ann Rheum Dis 2009;68:484-9

Technic of reporting L.R.+DAS28-CRP-AUC 23

% responders (ACR20)) 69

% good condition (DAS < 3.2) 71

Time to better (ACR20) condition 71

Time to good (DAS < 3.2) condition 113

Time to sustained better (ACR20) condition 39

Time to sustained good (DAS < 3.2) condition 57

Durability (unweighted Con Rew) 79



The doctor’s perspective(predictive validity)

Objective: to predict a subsequent « hard » end-point.

Methods: • Longitudinal study

• Technic: Likelihood ratio: Se/1-Spe

Successyes/no

Radiological progressionyes/no


Example: AIM trial

AnalysisRadiological progression at year 1

yes no

yes a b

no c d

Su

cces

s at

mo

nth

6

The highest L.R.+, the highest value of the technic

Radiological progression: changes after 1 year

Success at 6 months

Se = a/a+cSpe = d/b+dL.R. + = Se/1-Spe

The doctor’s perspective(predictive validity)


How to evaluate the clinical relevance of the technic of reporting? The doctor’s perspective

(capacity to predict a subsequent radiological progression)(example: AIM trial*)

Technic of reporting L.R.+

DAS28-CRP-AUC 0.54

% responders (ACR20)) 0.94

% good condition (DAS < 3.2) 1.37

Time to better (ACR20) condition 1.11

Time to good (DAS < 3.2) condition 1.30

Time to sustained better (ACR20) condition 1.24

Time to sustained good (DAS < 3.2) condition 1.34

Durability (unweighted Con Rew) 1.31

*Dougados M et al., Ann Rheum Dis 2009;68:484-9


How to switch a continuous into a dichotomous variable? The patient’s perspective

(face validity)

Objective: to correlate with the patient’s opinion.

Methods: • Longitudinal study

• Technic: Likelihood Ratio

Successyes/no

Patient’s good conditionyes/no


Patient’s opinion: at month 6, SF36 question #1: « in general, would you say that your health is poor, fair versus good, very good, excellent »

Patient’s good condition at month 6

yes no

yes a b

no c d

Su

cces

s a

t m

on

th 6

The highest L.R.+, the highest value of the technic

The patient’s perspective(capacity to correlate with the patient’s opinion)

Example: AIM trial

Evaluation:

Se = a/a+cSpe = d/b+dL.R.+ = Se/1-Spe


How to evaluate the clinical relevance of the technic of reporting? The patient’s perspective

(capacity to correlate with the patient’s opinion)(example: AIM trial*)

*Tubach F, …, Dougados M et al. Ann Rheum Dis 2005;64:34-7

Technic of reporting L.R.+DAS28-CRP-AUC 0.40

% responders (ACR20)) 1.27

% good condition (DAS < 3.2) 1.77

Time to better (ACR20) condition 1.31

Time to good (DAS < 3.2) condition 1.70

Time to sustained better (ACR20) condition 1.65

Time to sustained good (DAS < 3.2) condition 3.09

Durability good condition (unweighted Con Rew) 1.70


Conclusions (1/2)

1. Evaluation of binary variables (% success) is more clinically meaningful than evaluation of continuous variables (mean changes).

2. Evaluation of status is more clinically meaningful than evaluation of changes.

3. Time to success and sustainability of the success are important points to consider.


Conclusions (2/2)

It’s good to feel better but it’s better to feel good and even better if as soon as possible and for as long as possible.

maxime dougados paris-descartes university, medicine faculty; upres ea-4058; ap-hp, cochin hospital,...

Documents

months6030pain patient

continuous variable

dichotomous variable

technic of reporting

bettervariable pain

clinical relevance

absolute value of vas

study mcii minimum