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

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