Model-Based Meta-Analysis for Time Courses of Percent Responders in Diabetic
Peripheral Neuropathy, Postherpetic Neuralgia and Fibromyalgia Pain Trials
Chih-Wei Lin1, Wei Liu1, Walid Awni1, Sandeep Dutta1
1Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, IL, 60064, USA
RESULTS (CONTINUED)
BACKGROUND AND OBJECTIVES
Figure 2. Observed and Model-predicted (Solid Lines) Responder Rates for PHN
Treatments
• Common primary objectives in neuropathic pain trials, including diabetic
peripheral neuropathy (DPN), post-herpetic neuralgia (PHN) and fibromyalgia
(FM), are to investigate treatment difference from placebo and dose-response
relationship.
Pregabalin
30% reduction
Gabapentin
50% reduction
30% reduction
100
75
• Primary endpoint in these trials is usually mean pain score reduction from
baseline. Previously a meta-analysis by Othman et. al. (ACoP 2011) summarized
the dose-response relationships for neuropathic pain trials using mean pain score
reduction as efficacy endpoint.
0
75
%Responder
50
150
300
25
%Responder
Dose
(mg/day)
600
0
Trial
Number
100
• An important secondary endpoint that is also clinically relevant is responder rate.
Responder rate is used for evaluating treatment difference from placebo, and can
also be used to rank order drug response within or across classes.
25
2
4
6
8
10 12 14 0
2
4
6
8
100
%Responder
50
PHN
FM
5-13
Gabapentin
(alpha-2 delta )
3
9
892
0/1800/2400
4-10
Pregabalin
(alpha-2 delta)
6
19
1666
0/75/150/300/600
1-13
Duloxetine
(SNRI)
2
6
1027
0/20/60/120
12-26
Milnacipran
(SNRI)
4
11
3234
0/50/100/200
1-27
Pregabalin
(alpha-2 delta)
3
12
2002
0/150/300/450/600
8-14
31
96
12881
-
-
Total
P%Responder t , d drug   logit
-1
%Responder
t , d
drug
 , N t , d
drug
Trial
Number
6
8
10
4
8
12
16
20
24
7
28
Dose
(mg/day)
50% reduction
%Responder
75
Dose
(mg/day)
50
25
20
60
0
120
100
Trial
Number
75
5
50
9
25
200
0
50
Trial
Number
0
4
8
12 16 20 24 28 0
4
8
12 16 20 24 28
Time (weeks)
3
25
7
4
8
12 16 20 24 28 0
4
8
8
12 16 20 24 28
Trial
Number
Pregabalin
30% reduction
50% reduction
1
100
%Responder
2
75
4
50
Dose
(mg/day)
0
25
150
300
0
4
8
12
0
4
8
450
12
600
Table 3a. Estimated Responder Rates for DPN Treatments
Percent Responder at Maximum Suggested dose
Drug
ED50 Maximum Suggested
(mg/day)
Dose# (mg/day)
≥30% Reduction (95% CI)
≥ 50% Reduction (95% CI)
LOCF
BOCF
LOCF
BOCF
Placebo
-
0
43 (38-48)
34 (30-39)
29 (25-33)
22 (19-25)
Duloxetine*
9.2
60
59 (49-68)
50 (40-59)
43 (34-52)
35 (26-43)
Pregabalin*
270
300
53 (46-61)
44 (37-52)
38 (31-46)
29 (24-37)
*FDA labeled indication for DPN
• Evaluated drugs provide an additional 10%-16% increase in 30% responder rate
and 7%-13% increase in 50% responder rate for DPN over placebo effect.
Table 3b. Estimated Responder Rates for PHN Treatments
Percent Responder at Maximum Suggested dose
Drug
ED50 Maximum Suggested
(mg/day)
Dose# (mg/day)
≥30% Reduction (95% CI)
≥ 50% Reduction (95% CI)
LOCF
BOCF
LOCF
BOCF
Placebo
-
0
30 (23-39)
22 (17-28)
17 (13-23)
12 (9-15)
Gabapentin*
2200
1800
49 (35-66)
38 (26-54)
31 (21-47)
23 (15-36)
Pregabalin*
180
300
56 (40-73)
45 (30-63)
38 (24-56)
28 (17-44)
*FDA labeled indication for PHN
• Evaluated drugs provide an additional 16%-23% increase in 30% responder rate
and 11%-16% increase in 50% responder rate for PHN over placebo effect.
Table 3c. Estimated Responder Rates for FM Treatments

  1  exp   k  t 
 
Percent Responder at Maximum Suggested dose
Drug
ED50 Maximum Suggested
(mg/day)
Dose# (mg/day)
≥30% Reduction (95% CI)
≥ 50% Reduction (95% CI)
LOCF
BOCF
LOCF
BOCF
Placebo
-
0
31 (27-35)
26 (23-29)
19 (16-22)
15 (13-18)
Duloxetine*
3.9
60
42 (33-48)
36 (28-42)
27 (20-33)
23 (17-27)
Milnacipran*
68
200
40 (35-46)
34 (30-39)
26 (22-31)
21 (18-25)
Pregabalin*
120
450
40 (34-47)
35 (29-40)
26 (21-31)
22 (17-26)
*FDA labeled indication for FM
• Evaluated drugs provide an additional 8%-10% increase in 30% responder rate and
6%-8% increase in 50% responder rate for FM over placebo effect.
Table 4. Estimated Durations to achieve 50% and 97% effect for DNP, PHN and FM
• The correlation between observations within an arm was evaluated by a
compound symmetry correlation structure.
• Analyses were performed in S-PLUS 8.1 and graphs were created in R 2.14.1.
Parameter
DPN
PHN
FM
Time to achieve 50% effect (wk)
1.0
1.7
1.7
Time to achieve 97% effect (wk)
5.0
8.5
8.5
• The times to achieve drug effect plateau for DPN, PHN and FM were estimated to
be 5.0, 8.5, and 8.5 weeks.
RESULTS
SUMMARY
Table 2. Parameter Estimate
• The placebo response rate for 30% pain reduction (BOCF) was estimated to be
22%-34%, and for 50% pain reduction was estimated to be 12%-22% for DPN, PHN
and FM.
Model Parameter
DPN
PHN
FM
E0_30%reduction
-0.65
-1.3
-1.1
E0_50%reduction
-1.3
-2.0
-1.7
Emax
0.79
1.8
0.55
LNED50 Duloxetine
2.2
-
1.4
LNED50 Pregabalin
5.6
5.2
4.8
LNED50 Gabapentin
-
7.7
-
LNED50 Milnacipran
-
-
4.2
LOCF effect
0.37
0.44
0.25
• It takes 5 to 8 weeks to maximize drug effect for DPN, PHN or FM.
k
0.69
0.41
0.41
• Response rate is 4%-11% higher using LOCF imputation than BOCF.
ωBT (SD)
0.25
0.27
0.21
ρ (Within arm correlation)
0.60
0.47
0.02
• Evaluated drugs provide an additional 8%-23% increase in 30% responder rate and
6%-16% increase in 50% responder rate for DPN, PHN, and FM over placebo
effect.
• Response rate over placebo are higher (3%-13%) in PHN than DNP and FM.
• Among approved drugs, at their maximum approved doses
• Duloxetine showed the highest BOCF responder rate in DPN with estimated rates
of 50% and 35% to achieve 30% and 50% pain reduction.
Figure 1. Observed and Model-predicted (Solid Lines) Responder Rates for DPN
Treatments
Duloxetine
30% reduction
Pregabalin
50% reduction
30% reduction
100
50% reduction
100
75
50
Dose
(mg/day)
75
0
50
75
150
300
60
120
0
100
Trial
Number
75
9
25
Trial
Number
0
1
100
2
75
3
10
50
11
13
25
• Duloxetine gave the highest BOCF responder rate in FM with estimated rates of
36% and 23% to achieve 30% and 50% pain reduction.
600
%Responder
25
Dose
(mg/day)
• Pregabalin had the highest BOCF responder rate in PHN with estimated rates of
45% and 28% to achieve 30% and 50% pain reduction.
0
20
4
50
5
6
25
CONCLUSIONS
These results suggest the trial durations for DPN, PHN and FM of at least 5 to 8
weeks would be required to maximize the separations of pain response between
drugs included in this analysis from placebo. Duloxetine was most efficacious in
DPN and FM, while pregabalin was most efficacious in PHN.
7
0
8
0
0
2
4
6
8
10 12
0
2
Time (weeks)
4
6
8
10 12
0
2
4
6
8
10 12
0
2
Time (weeks)
4
6
8
10 12
2400
50% reduction
Time (weeks)
• Where:
Nresponder(t,ddrug): number of responders at time t receiving daily drug dose of ddrug;
P%responder(t, ddrug): probability of responders at time t receiving daily drug dose
ddrug;
N(t, ddrug): number of subjects at time t receiving daily drug dose ddrug;
E0,endpt: placebo response for 30% or 50% responder rate in the logit domain;
ηtrial: random effect to account for between trial variability;
ILOCF: effect of LOCF imputation over BOCF;
Emax: maximum pain reduction effect;
LNED50,drug: dose to achieve 50% maximum response in log scale;
k: rate constant for the accumulation of pain reduction effect.
%Responder
6
0
0


( E max  d drug )
E
  trial  I LOCF 
 0 , endpt
d drug  exp  LNED 50 , drug

4
75
%Responder
25
0
• The responder rates for different times and doses were described by a model that
combined an inverse logit Emax mixed function to characterize the dose-response
relationships, and a cumulative exponential function to describe the time course
of the responder rate for each indication.
P
2
6
• In the final model the number of responders for each indication was described by
a binomial distribution.
N responder t , d drug  ~ binomial
0
0
100
1-12
0/75/150/300/600
10
100
200
100
Time Course
(weeks)
2735
8
100
Time (weeks)
27
6
30% reduction
50
75
30% reduction
Table 1. Summary of Analyzed Neuropathic Pain Trials
9
4
0
0
Pregabalin
(alpha-2 delta)
2
Time (weeks)
Dose
(mg/day)
30% reduction
• A MBMA was conducted to describe the time courses of 30% or 50% pain
reduction responder rate over the treatment period and the dose-response
relationship for the drugs used in the trials. The effect of using baseline
observation carried forward (BOCF) or last observation carried forward (LOCF)
imputation on responder rates was also evaluated.
DPN
0
Gabapentin
Milnacipran
• The initial database included summary-level efficacy and safety data for 81 trials.
Based on efficacy endpoints, imputation methods and medications of interest, the
final analyzed data contained summary level data from 31 trials in ~13000 subjects
for 4 medications approved by FDA for treating neuropathic pain: duloxetine,
pregabalin, gabapentin, and milnacipran.
0/20/60/120
1800
0
Figure 3. Observed and Model-predicted (Solid Lines) Responder Rates for FM
Treatments
• A database was developed by a systemic search for all publicly available efficacy
and safety information on drugs evaluated for treatment of neuropathic pain
including DPN, PHN or FM.
1325
0
10 12 14
Time (weeks)
12
25
Time (weeks)
0
4
Dose
(mg/day)
7
0
METHODS
Duloxetine
(SNRI)
50
6
0
Dose (mg/day)
9
5
• The objective of this work was to characterize the time courses of percent
responders and relative efficacy of medications evaluated in clinical trials for
neuropathic pain using a model-based meta-analysis (MBMA).
Trials (n) Arms (n) Subjects (n)
8
75
4
50
• Meta-analyses of responder rate typically use only the response rate at study
endpoint for comparing different regimens. Dose vs. response-rate relationships
and the time course of responder rate across trials have not been fully
investigated.
Drug
3
2
0
Indication
100
1
75
Trial
Number
50% reduction
12
DISCLOSURE
The study design, study conduct, analysis, and financial support of the study were provided by AbbVie and
AbbVie personnel were involved in the writing, reviewing and approving of this publication. Chih-Wei Lin,
Wei Liu, Sandeep Dutta and Walid Awni are employees of AbbVie.