Transcript Molecular pathogenesis of Muscle wasting and regeneration

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
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•
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•
•
•
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