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
Novartis, data on file
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
Novartis, data on file
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
*
* * ** * * * * * *
* *
Novartis, data on file
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
Müller-Lissner et al. 2001
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
Novartis, data on file
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
Novartis, data on file
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
Müller-Lissner et al. 2001
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
Novartis, data on file
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
Müller-Lissner et al. 2001
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
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