IMMPACT-VIII Single-dose and short-term Proof of Concept trials in Neuropathic Pain
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Transcript of IMMPACT-VIII Single-dose and short-term Proof of Concept trials in Neuropathic Pain
IMMPACT-VIII
Single-dose and short-term Proof of Concept trials
in Neuropathic Pain
Srinivasa N. Raja
Johns Hopkins University
Proof of Concept StudiesNew 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
Single fixed dose-based on body weight over 60 minInfusion pain rating correlated with MS blood levels, but not lidocaine levels
Rowbotham MC et al. Neurol 1991;41:1024
PHNPlaceboOpioidLidocaine
Wu et al. Anesthesiology 2002;96:841-848
P<0.001 P=0.08P=0.88
P=0.001
PlaceboDiphenhydramine
50 mg
Morphine0.25mg/kg
Lidocaine5 mg/kg
Pre Post Pre Post Pre PostP
ain
Sco
re o
n N
um
eric
R
atin
g S
cale
(0-
10)
0
2
4
6
8
10 Phantom Pain
N=19
Single dose infusion cross-over trials: Pros and Cons
PROCON
• Minimizes effects of inter-subject variability
• Fewer subjects required• Early signal to help predict efficacy• Short study duration
• 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
Postamputation Pain: Oral morphine vs mexiletine on pain intensity ratings (3-period crossover)
Placebo Maintenance Pain ScoreOpioid Maintenance Pain ScoreMexiletine Maintenance Pain Score
*
Mexiletinen=42
Pai
n S
core
on
Nu
mer
ic
Rat
ing
Sca
le (
0-10
)
0
2
4
6
8
10
P<0.001 P<0.001
*
Placebo n=43
Opioidn=50
*
Wu et al.Anesthesiology 2008 (in press)
Can topical therapies be effective in neuropathic pain?
Rowbotham et al., Pain 1996;65:39
Vehicle and Lidocaine patches for 12 hrs vs Observation aloneOutcome measure: Change in VAS scores of pain
Single-dose cross-over design with vehicle control
Single dose cross-over trials with topical agents: Balancing the pros and cons
• Helps establish new routes of therapy, mechanistic implications?•Minimizes effects of inter-subject variability• Fewer subjects required• Early signal to help predict efficacy• Short study duration
PRO
• 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
CON
Predicting responders? Variability in Opioid Response: PHN Trial
Tella et al. 2007, Proceedings of 11th World Congress on Pain
5 10 15 20 25 30 35 40 45 50 55 60 65
-40
-20
0
20
40
60
80
100
Dec
reas
e in
Pai
n I
nte
nsi
ty,
%
Subject No.
Side EffectsLack of response
• Quantitative Sensory Testing
– Heat pain sensitivity at unaffected site prior to opioid exposure (baseline)
Predictors of Opioid Response in PHN: Phenotype: Heat pain threshold at unaffected site
Edwards R et al. Anesthesiology 2006;104:1243
Bas
elin
e H
eat
Pai
n T
hre
sho
ld,
°C
41
42
43
44
45
46
47
48
<30%Pain
Reduction
≥30%Pain
Reduction
<30%Pain
Relief
≥30%Pain
Relief
*
†P=0.04 P=0.09
Post-hoc analysis prospective studyIs this a phenotype for a genetic polymorphism? e.g., MOR
P<0.001
P<0.001
Placebo Opioid TCA
Pai
n In
ten
sity
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Deafferentation Subtype
Irritable Nociceptor PHN subgroup of patients more responsive to opioids
Irritable Nociceptor PHN(Intact C-fibers)
Placebo Opioid TCA0.0
0.5
1.0
1.5
2.0
2.5
3.0P<0.001
P=0.04
Pai
n In
ten
sity
P<0.04
TCA=Tricyclic antidepressant.Tella et al. IASP 11th World Congress on Pain; 2005.
P=0.86
Testing novel formulations of existing drugAbuse-deterrent opioid (ALO-01/Embeda)
• Healthy men and women, non-dependent recreational opioid users aged 18 to 55 years
• Ability to tolerate single dose of 120 mg of morphine sulfate andto distinguish morphine from placebo (2-day crossover design)
Screening
MSS
Placebo
Randomization
Placebo
MSS
MSS = morphine sulfate solution.
3-phase study: Screening/Qualifying, Treatment, Followup
Jones et al. 2008, APS and AAPMAdapted from Stauffer J. 2008
43+ 32
Treatment Phase Study DesignRandomized, double-blind, triple-dummy, 4-way crossover
Jones et al. 2008, APS and AAPM
ALO-01W
ALO-01C
MSS
MSS
MSSPlaceboALO-01CALO-01W
ALO-01W
ALO-01W Placebo
ALO-01C
Placebo
MSS
ALO-01C
Placebo
Session 1 Session 2 Session 3 Session 4 Post-treatment Follow-up
Washout
14-21d
Washout
14-21d
Washout
14-21d
Safety Assessments
Capsules, crushed pellets in apple juice, and apple juice
Outcomes: PK and PD measures (subjective and objective measures)
Negative control Positive control
Aim: If study drug taken intact less desirable than crushed capsule or MS sol. for recreation users
POC Designs: Two phase studyDronabinol as adjuvant for patients on opioid therapy
Narang et al. J Pain 9;245:2008
PlaceboN=29
20 mg DBN=29
10 mg DBN=30
RandomizedN=30
ScreenedN=160
Phase IDouble-blind, randomized,Placebo-controlled, 3 periodSingle-dose croosover studyThree 8-hour visits
4-wk Multi-doseN=28
5-60 mg/ day
Phase IIOpen-label, extensionMulti-dose studyAll patients offered entry
Chronic non-cancer pain on stable opioid
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
Byas-Smith et al., Pain 1995
Stage 1- 3-period crossover
N=41
Stage 2- Four double blind randomized1 wk treatment periods
12 responders
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
Activetreatment
Placebotreatment
randomize NIdeal Design:
randomized allocation, blinding, measurements of outcomes, formal statistical analysis
Ideal Drug: Rapid onset, rapid offset, reversible actionIdeal Disease: Stable pain over long duration
Activetreatment
Placebotreatment
Assessment Patient preference
Scuffham PA Value in Health 11;97:2008
N of 1 trials: the pros and cons
•Minimizes effects of inter-subject variability•Potential to identify subset of patients who are responders•Can influence clinical decision for the patient•Has been used for cost-benefit analysis
PRO
•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
CON
Australian studies: to improve access to selected high cost medicationsCelecoxib vs sustained release paracetamol for osteoarthritisGabapentin 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
• 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
De Grandis and Minardi Drugs R&D 2002; 3:223
***
VA
S
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 recommendationsDworkin RH et al Pain 2005;113:9
37.4%
Validating a measure of function:Pain relief with Opioids objective increase in activity
Agarwal S et al. Pain Medicine 2007; 8:554-62
Transdermal fentanyl- 25-150 mcg/h
Intent to treat: 33.7 + 14%decrease in pain
Early stage drug developmentSensitivity vs Specificity
• Wrong disease state• Wrong dose• Wrong duration of treatment (exposure-
response 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
1980-84
1995-99
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
Cross et al., 2002Pharmacoepidemiol & Drug safety
• Smallest dose that produces near maximal effect rather than maximal tolerated dose
Median6.5 yr
2.5 yr
Lessons learnt from failed neuropathic pain RCTsRelation 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;70:263Polydefkis 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
AcademiaNIH
RegulatoryAgencies
Industry
StakeholdersPatientsHealth-care providersInsurersIndustryAgencies