yychen_migraine ppt
TRANSCRIPT
Redundancy of Long-term Clinical Trial Endpoint when Testing
Migraine Acute Treatment
Yen-Yu, Chen (Shafy)MSc Clinical Pharmacology 2016
27th September, 2016
Migraine is a disease… Headache
Whole body
Nausea and vomiting
May include Aura
Aura: Fortification spectrum(Wilkinson & Robinson, 1985)
Four-point pain scale
Pain Free Mild Moderate Severe
0 1 2 3
Treatment success: pain score from 3 / 2 to 1 / 0.
Efficacy endpoint: a variable to measure drug effect.
In this case binary: success or failure.
Efficacy endpoint in migraine trial
2 h pain relief: Migraine severity from 3/ 2 to 1/ 0, 2 h post-dose No vomiting and no aura
24 h sustained pain relief: Migraine severity from 3/ 2 to 1/ 0, 2-24 h post-dose No second dose of study drug No rescue medication No headache recurrence
Therapeutic gain, therapeutic ratio, and the number needed to treat
Placebo Active0
10
20
30
40
50
60
70
30
60
The percentage of 2 hours pain Relief (%)
2 h pain relief in placebo and active
Resp
onse
rate
(%)
Active response rate: ARR
Placebo response rate: PRR
Therapeutic gain (TG)= ARR – PRR
Therapeutic ratio (TR)= ARR / PRR
Number needed to treat (NNT)= 1/TG
Therapeutic gain, therapeutic ratio, and the number needed to treat
Placebo Active0
10
20
30
40
50
60
70
30
60
The percentage of 2 hours pain Relief (%)
2 h pain relief in placebo and active
Resp
onse
rate
(%)
In this case:
ARR = 60 %
PRR = 30 %
TG = 60 % - 30 % = 30 %
TR = (60 %) / (30 %) = 2
NNT = 1 / (30 %) = 3.3
Is that needed?
Originally:
Regulatory approval: 2 h pain relief
Now: 24 h sustained pain relief Longer, more expensive study But more like ordinary clinical care
Methodologyn = 85
1991-2015, Migraine, Placebo-Controlled
Trials (PCTs), Triptans
Cluster Headache: 2
No Efficacy Related PCTs: 4
No Triptans: 10
n = 69Migraine, PCTs,
with Triptans
No Suitable Endpoint: 3 Disability Measurement: 1
Reduce 50% at 2 h: 1
Motion Sickness Assessment:1
Not Compared Triptan and Placebo Only: 3
Encapsulated Study Drug: 3
Lack of Suitable Data:
21
Only 4h Data: 2
No 24 h Data: 14
No 2 h/ 24 h Data: 5
n = 39Migraine, PCTs, with 2 h and 24 h 4-Point Pain Score Related Data
Adolescents2 h/ 24 h Pain Relief: 3
Into Subanalysis
2 h Pain Relief + 24 h Pain Free: 1
2 h Pain Free + 24 h Pain Relief: 1
2 h/ 24 h Pain Free: 6
2 h Pain Relief + 24 h Headache Recurrence: 17
n= 11Migraine, PCTs, with 2 h and 24 h Pain Relief Data, based
on Headache Severity 4-Point Pain Scale
Into Analysis.
Adult result of therapeutic gain (TG)
0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00 0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
50.00
f(x) = 0.727630236808162 x + 11.5705477774418R² = 0.876466246872391
Therapeutic Gain (%) 24 h to 2 h, (n = 22)
Therapeutic Gain 24 h (%)
The
rape
utic
Gai
n 2
h (%
)
Adult result of therapeutic ratio (TR)
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 0.00
0.50
1.00
1.50
2.00
2.50
3.00
3.50
f(x) = 0.277943243197083 x + 1.1733496778259R² = 0.865053425282158
Therapeutic Ratio 24 h to 2 h, (n = 22)
Therapeutic Ratio 24 h
The
rape
utic
Rat
io 2
h
Adult result of number needed to treat (NNT)
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
f(x) = 0.246123824439742 x + 2.40218931825032R² = 0.613649559020224f(x) = 1.84412085697113 ln(x) + 0.866583677259985R² = 0.787476827239864
Number Needed to Treat 24 h to 2 h, (n = 22)
Number Needed to Treat 24 h
Num
ber
Nee
ded
to T
reat
2 h
Mean response rate of adults and adolescents in 2 h and 24 h
1 2 3 40
10
20
30
40
50
60
70
35.15
21.6
56.48
46.27
64.19
45.62
66.57
57.93
Mean Response Rate of Adults and Adolescents in 2 h and 24 h
Placebo Active Drug
Mea
n R
espo
nse
Rat
e (%
)
Adults 2 h Adults 24 h Adolescents 2 h Adolescents 24 h
Conclusion
Adults 2 h pain relief can predict 24 h sustained pain relief
Adolescents 24 h sustained pain relief does not work at all
(possible reason: shorter attack)
Therefore, the testing of this long-term efficacy endpoint is
redundant.
Thanks for your attention!