clinical efficacy

Zelmac : clinical efficacy

How do we measure clinical efficacy?

Zelmac: phase III study designs

Baselineperiod

Treatment period6 mg b.i.d. or placebo

Withdrawalperiod

Baselineperiod

Treatment period2 mg b.i.d., 6 mg b.i.d.

or placebo

4 weeks 12 weeks 4 weeks

Studies 1 and 2

Study 3

How can you “measure” drug response?

Abdominal pain?

Bloating??

Constipation?

Subject’s Global Assessment of Relief

Please consider how you felt this past week in regard to your IBS, inparticular your overall wellbeing, and symptoms of abdominaldiscomfort, pain and altered bowel habit

Compared to the way you usually felt before entering the study, howwould you rate your relief symptoms during the past week?

Completely relieved Considerably relieved Somewhat relieved Unchanged Worse

Response: ≥50% complete/considerable relief or 100% somewhatrelief at study endpoint

Novartis, data on file

Validation of Subject’s Global Assessment of Relief

Last study week

Efficacy variablechange from baseline (%) Complete Considerable Somewhat Unchanged Worse

Abdominal pain/discomfort –79 –50 –23 –5 8

Days with significant pain –73 –40 –7 18 3

Daily pain score –72 –44 –16 4 8

Days with significantbloating –61 –37 –7 6 3

Daily bloating score –64 –41 –16 1 7

Bowel habit –75 –50 –23 –3 6

Days with no bowelmovement –62 –46 –28 –10 –16

Days with hard orvery hard stool –71 –70 –50 –19 3

Study 2 n=799 Novartis, data on file

Demographics and baseline characteristics

Studies 1, 2 and 3

Variable

Mean age (years) 42.9

Gender (% female) 91.8

Race (% Caucasian) 85.5

Mean days with abdominal pain/discomfort (%) 89.0

Mean days with bloating (%) 89.9

Mean no. of bowel movements/week 5.6

Mean stool consistency score 4.8

Mean duration of IBS (years) 14.6


Global assessment: responders

0

10

20

30

40

50

60

70

80

** *

* * * ** *

Pat

ien

ts w

ith

at

leas

tso

mew

hat

rel

ief

(%)

Week

*

Study 1n=881*p<0.05 (6 mg b.i.d. vs placebo)

*

Zelmac 6 mg b.i.d.

Placebo

Start of treatment

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

Müller-Lissner et al. 2001

Global assessment: responders

0

10

20

30

40

50

60

70 **

* ** ** ** * *

Withdrawal week

–4 –3 –2 –1 1 2 3 4 5 6 7 8 9 10 11 12 W1 W2 W3 W4

Study 3n=1,519*p<0.05 (6 mg b.i.d. vs placebo)

Start of treatment

Zelmac 6 mg b.i.d.

PlaceboPat

ien

ts w

ith

at

leas

tso

mew

hat

rel

ief

(%)

Week


Early onset of action: bowel movements

Day

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0

Mea

n n

um

ber

of

bo

wel

m

ove

men

ts/d

ay

Start of treatmentPooled data, Studies 1 and 2n=1,116*p<0.05 (6 mg b.i.d. vs placebo)

Zelmac 6 mg b.i.d.

Placebo

–7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6 7 8 9 10 11 12 13 14

*

* * ** * * * * * *

* *


Sustained action: bowel movementsM

ean

nu

mb

er o

f b

ow

el

mo

vem

ents

per

wee

k

9

8

7

6

5

0

Week

* * ***

*

* **

Start of treatmentStudy 1n=881*p<0.05 (6 mg b.i.d. vs placebo)

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

Zelmac 6 mg b.i.d.

Placebo


Early onset of action: stool consistency

Pooled data, Studies 1 and 2n=1,116 *p<0.05 (6 mg b.i.d. vs placebo)

Mea

n s

too

l co

nsi

sten

cy s

core

–7 –5 –3 –1 2 4 6 8 10 12 14

Day

*

** * * * * * * * * * *

*

Start of treatment

5.0

4.5

4.0

3.5

3.0

0

Zelmac 6 mg b.i.d.

Placebo


Early onset of action: abdominal pain/discomfort

Mea

n p

ain

sco

re

–7 –5 –3 –1 2 4 6 8 10 12 14

Day

* * * ** * *

** * *

Pooled data, Studies 1 and 2n=1,116*p<0.05 (6 mg b.i.d. vs placebo)

Start of treatment

3.2

3.0

2.8

2.6

2.4

2.2

0

Zelmac 6 mg b.i.d.

Placebo


Sustained action:abdominal pain/discomfort

Mea

n p

ain

sco

re

(ch

ang

e fr

om

bas

elin

e)

*

* ** * *

* * * *

*

0

–0.2

–0.4

–0.6

–0.8

–1.0Study 1n=881*p<0.05 (6 mg b.i.d. vs placebo)

Week

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

Zelmac 6 mg b.i.d.

Placebo


Sustained action: abdominal pain/discomfort

0

–0.2

–0.4

–0.6

–0.8

–1.0

–1.2

–1.4

Mea

n p

ain

sco

re (

chan

ge

fro

m b

asel

ine)

Week

Study 3n=1,519*p<0.05 (6 mg b.i.d. vs placebo)

Withdrawal week

*

* ** * *

* **

Zelmac 6 mg b.i.d.

Placebo

0 1 2 3 4 5 6 7 8 9 10 11 12 W1 W2 W3 W4


Sustained action: bloating

Mea

n b

loat

ing

sco

re

(ch

ang

e fr

om

bas

elin

e)

*

**

**

* * **

0

–0.2

–0.4

–0.6

–0.8

–1.0Study 1n=881*p<0.05 (6 mg b.i.d. vs placebo)

Week

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

Zelmac 6 mg b.i.d.

Placebo


What about the placebo Response?

Several clinical trials in functional GI disorders have shown a high placebo

response rate, defined as the “psychological or psychophysiologic

effect produced by placebo”

IBS is a functional Disease

In a meta-analysis, Spiller reported placebo response rates of up to 84% in 25 randomized, controlled studies in IBS, conducted during a 22-year period.

He found that, on average, the placebo response is approximately three times the size of the difference between drug and placebo response

Spiller Asked the same question

But Why??

Can you explain the phenomena based on the nature of the disease?

No One still knows

“patient- care effect”

Patient Research Staff

Symptoms, worries, concerns

accept and validate

comfort

decrease anxiety

Summary of Zelmac efficacy

Zelmac 6 mg b.i.d. provides rapid and sustained relief of three key symptoms of IBS with constipation

– abdominal pain/discomfort

– bloating

– constipation

Zelmac provides a significant improvement in the Subject’s Global Assessment of Relief

These improvements occur within the first week of treatment and are sustained for the duration of treatment

clinical efficacy

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