1. Proof-of-Concept Studies in Non- Neuropathic Pain IMMPACT Meeting Washington, D.C. June 13, 2007 Nathaniel Katz, MD, MS, Analgesic Research, Needham, MA, USA

2. 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?

3. 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.govhttp://symptomresearch.nih.gov

4. Literature Review: Early Onset Randomized controlled trials in OA or RA Superior efficacy against control demonstrated within 2 weeks English language

5. 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

6. Can efficacy be demonstrated in POC studies in chronic visceral pain?

7. Statistical significance of a κ-opioid agonist for chronic pancreatitis, n=6 Eisenach JC et al, Pain, 2003

8. Does dense data capture of pain scores improve assay sensitivity?

9. Pairwise Comparison / Data Set Difference in Mean Experimental Score Between Treatment Groups (adjusted for baseline) Standard Deviation of the Difference (SDD) P valueRelative Sample Size (%) Weekly phone check data -8.95.960.16100 1 per day-7.35.550.2187 2 per day-10.34.770.0564 4 per day-9.54.800.0765 8 per day-9.44.650.0661 16 per day-9.84.680.0562 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

10. Does assessment of evoked pain improve assay sensitivity?

11. “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

12. Do composite outcome measures have more assay sensitivity than single measures?

13. 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

14. Do multi-period within-patient crossover studies improve assay sensitivity?

15. 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 SPID 60 : 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

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

17. 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 TOTPAR 8 : 10 mg (p<0.05), 20 mg (p<0.01) Narang S et al, J Pain, 2008

18. Accurate pain reporting Patient Instrument Report + Validity Reliability Responsiveness

19. 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

20. Psychophysical assessment

21. Accurate pain reporter Coefficient of Variation = 0.49R 2 = 0.82

22. Inaccurate pain reporter Coefficient of Variation = 1.23 R 2 = 0.53

23. 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

24. 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.

25. Actogram Running Swimming Office work-desk Walking Preparing dinner Couch sitting; reading In bed; reading Sleeping Got up Getting ready Walking Office work-desk

26. 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