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IMMPACT-VIII Single-dose and short-term Proof of Concept trials in Neuropathic Pain Srinivasa N. Raja Johns Hopkins University Proof of Concept Studies New Drug Development • Early stage clinical drug development of a compound that has shown potential in animal models and early safety testing • Help make an early Go-No Go decision POC studies in Neuropathic Pain Potential uses • Is neuropathic pain resistant to certain drugs? – Opioids in neuropathic pain (PHN and postamputation pains) • Test a new route of therapy/ site of action-Topical lidocaine/capsaicin • Are there predictors of drug effects? – Genetic polymorphisms, Pain mechanisms • Testing novel formulations of an existing drug for better safety – Abuse deterrent opioids • Can neuropathic pain be prevented or the disease modified? – Persistent post-surgical NP pain; Diabetic neuropathy and dietary supplements • Testing and validating objective measures of drug effects Is neuropathic pain resistant to opioids? I.V. morphine and lidocaine infusions in PHN and Phantom Pain: 3-session double-blind cross-over studies 10 Pain Score on Numeric Rating Scale (0-10) PHN P=0.001 P=0.88 P<0.001 6 P=0.08 4 Pre Post Pre Post Pre Post 0 Single fixed dose-based on body weight over 60 min Infusion pain rating correlated with MS blood levels, but not lidocaine levels Rowbotham MC et al. Neurol 1991;41:1024 Phantom Pain 8 2 N=19 Placebo Opioid Lidocaine Placebo Morphine Lidocaine Diphenhydramine 0.25mg/kg 5 mg/kg 50 mg Wu et al. Anesthesiology 2002;96:841-848 Single dose infusion cross-over trials: Pros and Cons • Minimizes effects of inter-subject variability • Fewer subjects required • Early signal to help predict efficacy • Short study duration PRO • Slow offset or prolonged duration of effect may lead to carry over effects • May not help predict side effects • No information on oral bio-availability • No dose-response information • May miss effect if inappropriate dose chosen CON Postamputation Pain: Oral morphine vs mexiletine on pain intensity ratings (3-period crossover) Pain Score on Numeric Rating Scale (0-10) 10 Wu et al. Anesthesiology 2008 (in press) Placebo Maintenance Pain Score Opioid Maintenance Pain Score Mexiletine Maintenance Pain Score P<0.001 P<0.001 8 6 * * * 4 2 0 Placebo n=43 Opioid n=50 Mexiletine n=42 Can topical therapies be effective in neuropathic pain? Single-dose cross-over design with vehicle control Vehicle and Lidocaine patches for 12 hrs vs Observation alone Outcome measure: Change in VAS scores of pain Rowbotham et al., Pain 1996;65:39 Single dose cross-over trials with topical agents: Balancing the pros and cons PRO • Helps establish new routes of therapy, mechanistic implications? •Minimizes effects of intersubject variability • Fewer subjects required • Early signal to help predict efficacy • Short study duration CON • Short duration of observation may not be predictive of long-term effects • May not help predict side effects with longer term treatment •No dose-response information Predicting responders? Decrease in Pain Intensity, % Variability in Opioid Response: PHN Trial 100 80 60 40 20 Side Effects Lack of response 0 -20 -40 5 10 15 20 25 30 35 40 45 50 55 60 65 Subject No. Tella et al. 2007, Proceedings of 11th World Congress on Pain Predictors of Opioid Response in PHN: • Quantitative Sensory Testing – Heat pain sensitivity at unaffected site prior to opioid exposure (baseline) Baseline Heat Pain Threshold, °C Phenotype: Heat pain threshold at unaffected site 48 47 P=0.04 46 * † P=0.09 45 44 43 42 41 <30% ≥30% Pain Pain Reduction Reduction Post-hoc analysis prospective study Is this a phenotype for a genetic polymorphism? e.g., MOR <30% Pain Relief ≥30% Pain Relief Edwards R et al. Anesthesiology 2006;104:1243 Irritable Nociceptor PHN subgroup of patients more responsive to opioids Deafferentation Subtype P<0.04 P=0.86 3.0 P<0.001 2.5 2.0 P=0.04 1.5 1.0 Pain Intensity Pain Intensity 3.0 Irritable Nociceptor PHN (Intact C-fibers) P<0.001 2.5 P<0.001 2.0 1.5 1.0 0.5 0.5 0.0 Placebo Opioid 0.0 Placebo Opioid TCA TCA TCA=Tricyclic antidepressant. Tella et al. IASP 11th World Congress on Pain; 2005. Testing novel formulations of existing drug Abuse-deterrent opioid (ALO-01/Embeda) 3-phase study: Screening/Qualifying, Treatment, Followup • Healthy men and women, non-dependent recreational opioid users aged 18 to 55 years MSS Placebo 43+ Screening Placebo Randomization 32 MSS • Ability to tolerate single dose of 120 mg of morphine sulfate and to distinguish morphine from placebo (2-day crossover design) Jones et al. 2008, APS and AAPM MSS = morphine sulfate solution. Adapted from Stauffer J. 2008 Treatment Phase Study Design Randomized, double-blind, triple-dummy, 4-way crossover Aim: If study drug taken intact less desirable than crushed capsule or MS sol. for recreation users Capsules, crushed pellets in apple juice, and apple juice Washout Washout Washout Session 2 Session 1 14-21d Session 3 Session 4 Post-treatment Follow-up 14-21d Positive control 14-21d Negative control ALO-01W ALO-01C Placebo MSS ALO-01C MSS ALO-01W Placebo MSS Placebo ALO-01C ALO-01W Placebo ALO-01W MSS ALO-01C Safety Assessments Outcomes: PK and PD measures (subjective and objective measures) Jones et al. 2008, APS and AAPM POC Designs: Two phase study Dronabinol as adjuvant for patients on opioid therapy Screened N=160 Chronic noncancer pain on stable opioid Randomized N=30 Placebo N=29 4-wk Multi-dose N=28 5-60 mg/ day 10 mg DB N=30 20 mg DB N=29 Phase I Double-blind, randomized, Placebo-controlled, 3 period Single-dose croosover study Three 8-hour visits Phase II Open-label, extension Multi-dose study All patients offered entry Narang et al. J Pain 9;245:2008 Pros and Cons • Single dose cross-over design established a POC of effects as an adjuvant analgesic with a small N • Established that higher dose not associated with better pain relief but more common side effects • Pain relief sustained during the open label phase • Limitations – Effectiveness demonstrated only as an adjuvant – Open label phase II could be non-specific- no placebo control – Design useful only for drugs with rapid onset of action Enriched study: Clonidine in diabetic neuropathy • Two stage design- Selection and Efficacy 12 responders N=41 Stage 1- 3-period crossover Byas-Smith et al., Pain 1995 Stage 2- Four double blind randomized 1 wk treatment periods N of 1 or single-patient designs • To test statistically within a single patient whether or not an intervention improves clinical outcome • Within patient response vs group response Individual patient Active Placebo treatment treatment Assessment Patient preference Active Placebo treatment treatment randomize Ideal Design: randomized allocation, blinding, measurements of outcomes, formal statistical analysis Ideal Drug: Rapid onset, rapid offset, reversible action Ideal Disease: Stable pain over long duration N Scuffham PA Value in Health 11;97:2008 N of 1 trials: the pros and cons PRO •Minimizes effects of intersubject variability •Potential to identify subset of patients who are responders •Can influence clinical decision for the patient •Has been used for costbenefit analysis CON •Slow onset drug effects may lead to long duration study •Slow offset or prolonged duration of effect leads to carry over effects •Potential for drop out and less enthusiasm to continue with paired comparisons Australian studies: to improve access to selected high cost medications Celecoxib vs sustained release paracetamol for osteoarthritis Gabapentin vs placebo for neuropathic pain Scuffham PA Value in Health 11;97:2008 Is an ounce of prevention better than a pound of cure? NMDA antagonists for postmastectomy pain • Randomized D-B, PC trial in patients undergoing mastectomy, lumpectomy with axillary node dissection • Amantadine 100mg bid, day before to 14 day after surgery • Rescue drugs OK Eisenberg E. J Pain 2007;8;223 Prevention of disease progression and improved pain Acetyl-L-Carnitine in Diabetic Neuropathy 100 90 80 70 60 50 40 30 20 10 0 LAC Placebo * VAS • Double-blind placebo-controlled RCT in 333 subjects, 1 yr followup • 1 g im for 10 d, 2 g orally for 355 d • NCV (motor and sensory) and amplitude primary OM, pain secondary • 6m and12 m- NCV increased in active group in all nerves; decrease or no change in placebo • 199 pts had pain at baseline- 39% decrease at 12 m Pre ** 6 m 12 m De Grandis and Minardi Drugs R&D 2002; 3:223 Testing drugs for chronic pain Core outcome measures • Pain • Physical functioning – Multidimensional Pain Inventory Interference Scale – Brief Pain Inventory interference items • • • • Emotional functioning Participant rating of global improvement and satisfaction Symptoms and adverse events Patient disposition IMMPACT recommendations Dworkin RH et al Pain 2005;113:9 Validating a measure of function: Pain relief with Opioids objective increase in activity Transdermal fentanyl- 25-150 mcg/h 37.4% Intent to treat: 33.7 + 14% decrease in pain Agarwal S et al. Pain Medicine 2007; 8:554-62 Early stage drug development Sensitivity vs Specificity • Wrong disease state • Wrong dose • Wrong duration of treatment (exposureresponse relationship) • Outcome measure- no biomarkers (surrogate endpoint) for pain • Not considering the natural course of the disease- disease progression or regression • Active comparators with proven efficacy to distinguish negative from failed trials Dosage changes in new molecular entities approved between 1980-1999 • 499 NME, 354 evaluable • Dosage changes occurred in 21% of 354 NME post approval • 79% safety-motivated dosage decrease • 27% neuropharm. drugs • Smallest dose that produces near maximal effect rather than maximal tolerated dose 2.5 yr 1980-84 1995-99 Median 6.5 yr Cross et al., 2002 Pharmacoepidemiol & Drug safety Lessons learnt from failed neuropathic pain RCTs Relation to study characteristics • Aim: to identify factors associated with + vs – outcomes of placebo-controlled neuropathic pain trials • 106 clinical trials with 123 Rx-group comparisons + studies: medication response rates greater, placebo response lower, larger sample size, cross-over design, published earlier (1995 vs 1998.5) Greater placebo response: • greater medication response & trial duration, parallel design • -ve vs + outcome: 27% vs 16% placebo responders (>50%) Katz JK, Finnerup NB, Dworkin RH Neurology 2008;70:263 Polydefkis M, Raja SN Neurology 2008;70:250 Study Designs • • • • • • • • • Parallel vs Crossover Enriched enrollment design Excluding high placebo responders? N-of-1 studies Adaptive designs Time-to-exit designs (see Galer et al Pain 1999-Lido patch) Mechanism-based clinical studies (Wallace MS 2002 J Pain) Genetic screening: e.g. MOR polymorphism Split-trial strategy- pooled data from few centers with extensive testing Rowbotham M Neurology 2005;65:S67 Summary • Study design- adaptive, depending on nature of question being asked • Consider the balance of pros and cons of the design relative to the question New strategies to test and develop new drugs efficiently for neuropathic pain: A combined effort Stakeholders Patients Health-care providers Insurers Industry Agencies Academia NIH Regulatory Agencies Industry