Proof-of-Concept Studies in Non-

Neuropathic PainIMMPACT Meeting

Washington, D.C.

June 13, 2007

Nathaniel Katz, MD, MS, Analgesic Research, Needham, MA, USA

Key Questions Can we do informative efficacy studies in

small numbers of pain patients with non-neuropathic pain?

Can we demonstrate efficacy early? How? What are some methodological

features of successful studies?

Key Issues: ↑ Δ/σ Patients

Homogeneity of condition Training Enriched enrollment Pharmacogenomics

Site issues How many Site training

Study structure Crossover/parallel Treatment vs. withdrawal Duration

Dosing Dose vs. concentration

controlled Fixed, flexible, MTD

Control groups Outcome assessment

Cross-modality matching Composite endpoints Dense data capture

Statistical approaches Address covariates Information-based designs

Max M, http://symptomresearch.nih.gov

Literature Review: Early Onset Randomized controlled trials in OA or RA Superior efficacy against control

demonstrated within 2 weeks English language

Results Multiple studies (>20) readily identified Studies fell into two rough groups: small early short

crossover studies (1970s-1980s) and large parallel studies with early endpoints (1990s-2000s)

Interventions included NSAIDs, opioids, topicals, injections

Range of sample sizes: 19-1600 Four studies had < 30 subjects

Several studies demonstrated efficacy within hours

Can efficacy be demonstrated in POC studies in chronic

visceral pain?

Statistical significance of a κ-opioid agonist for chronic pancreatitis, n=6

Eisenach JC et al, Pain, 2003

Does dense data capture of pain scores improve assay

sensitivity?

Pairwise Comparison / Data Set

Difference in Mean Experimental Score Between Treatment Groups (adjusted for baseline)

Standard Deviation of the Difference (SDD)

P value Relative Sample Size (%)

Weekly phone check data

-8.9 5.96 0.16 100

1 per day -7.3 5.55 0.21 87

2 per day -10.3 4.77 0.05 64

4 per day -9.5 4.80 0.07 65

8 per day -9.4 4.65 0.06 61

16 per day -9.8 4.68 0.05 62

Table 3: Results of Analyses of Covariance (ANCOVA) based on Weekly Phone Check Data and Dense Data Capture in 19 Patients who used the LogPad, OraMorph vs. Naproxen

Jamison et al, 1998; Shapiro et al, 2003

Does assessment of evoked pain improve assay

sensitivity?

“Walking model” of knee OA pain 530 patients with

flared knee OA randomized to single doses of valdecoxib, rofecoxib, or placebo

Patients walked on treadmill multiple times over 6 hrs

Significant differences as early as 4 hrs

Moskowitz et al, Osteoarthritis & Cartilage, 2006

Do composite outcome measures have more assay

sensitivity than single measures?

Development of a responder index for LBP

Simon L et al, J Rheum, 2007

5 clinical trials of celecoxib or valdecoxib vs. placebo pooled

Combinations of VAS, PGA, and RMDQ explored for responsiveness

Do multi-period within-patient crossover studies improve

assay sensitivity?

FBT for breakthrough LBP Enriched enrollment, 9-period (6 active, 3

placebo) within-pt crossover design of 77 randomized pts (124 screened) of single doses of FBT vs. placebo

SPID60: FBT 8.3 (se=0.66)

Plabebo 3.6 (se=0.57)p<0.0001

80% power achieved with 20 subjects

Portenoy R, et al, CRMO, 2007

Single-dose add-on design in mixed chronic pain?

Efficacy of Dronabinol as an Adjuvant Treatment for Chronic Pain Patients on Opioid Therapy

3-period within-patient single-dose crossover design of dronabinol 10 or 20 mg vs. placebo in 30 pts with mixed chronic pain

All pts continued opioid therapy

TOTPAR8: 10 mg (p<0.05), 20 mg (p<0.01)

Narang S et al, J Pain, 2008

Accurate pain reporting

Patient Instrument

Report

+

• Validity• Reliability• Responsiveness

Neuropsychological battery Depression Anxiety Neuroticism Somatization Catastrophizing Hypervigilance Fear of Pain Pain Attitudes Expectation of pain relief Hopefulness for pain relief Quality of life Social desirability Locus of control

Psychophysical assessment

y = 8.5684x - 381.43

R2 = 0.8174

-40

-20

0

20

40

60

80

100

42 43 44 45 46 47 48 49 50 51 52

Trial1

Trial2

Trial3

Trial4

Trial5

Trial6

Trial7

Mean

Linear (Mean)

Accurate pain reporter

Coefficient of Variation = 0.49 R2 = 0.82

y = 2.4016x - 108.58

R2 = 0.5294

-20

-10

0

10

20

30

40

50

42 43 44 45 46 47 48 49 50 51 52

Trial1

Trial2

Trial3

Trial4

Trial5

Trial6

Trial7

Mean

Linear (Mean)

Inaccurate pain reporter

Coefficient of Variation = 1.23 R2 = 0.53

Forced choice thermal cross-modality matching: preliminary results 28 subjects with knee OA underwent pain

intensity assessment before and after a standard exercise intervention

24 subjects reported pain “worse” and 4 “better” Change in pain among the 24 “worse” subjects:

VAS: mean 0.43, sd 1.21, ses 0.36 FCT: mean 2.17, sd 2.80, ses 0.78

Composite endpoint of contemporaneously measured pain and physical activity

Comparison of pain-activity composites to pain and activity alone in knee OA patients N=60, 1-wk crossover Celecoxib vs. placebo

135 patients with knee OA recruited at single site in 5 mo.

ActogramRunning

Swimming

Office work-desk

Walking

Preparing dinner

Couch sitting; reading

In bed; reading

Sleeping

Got up

Getting ready

Walking

Office work-desk

Conclusions Small randomized controlled clinical trials can be

successfully completed, at single sites, with demonstration of efficacy within a day, in a variety of chronic pain syndromes

Add-on designs and heterogeneous patients are possible

Attention must be paid to a number of methodological issues

Further research is needed to address specific methodologic questions