NEUROPATHIC PAIN – OPTIMIZING PATIENT OUTCOME WITH COMBINATION THERAPY

Overview

OxyContin® tablets and gabapentin (GBT) – effectiveness in neuropathic pain

OXY3204 – a clinical review of OxyContin® tablets/GBT in combination

GBT – in Neuropathic Pain

1. Gilron et al., NEJM 2005

Gabapentin

Gabapentin (GBT) licensed for neuropathic pain in 2002 and available in > 50 countries

GBT has proven efficacy in a range of neuropathic pain types

Approximately 60% of neuropathic pain patients receive high dose GBT (≥ 1800 mg/day)

26–38% patients receive maximal doses of GBT (2207 mg/day) but not full pain resolution1

Oxycodone – in Neuropathic Pain

Oxycodone

1. Ballantyne Oncologist. 2003; 2. Dworkin et al., Arch Neurol. 2003; 3. Watson et al., Neurology 1998; 4. Watson et al., Pain 2003

Opioids have proven efficacy in neuropathic pain1

Opioids are recommended first-line therapy for neuropathic pain2

OxyContin® tablets provides significant reductions in global pain scores in PHN3

OxyContin® tablets significantly reduces pain in diabeticneuropathy and improves QoL4

OxyContin® has been licensed since 1994 and marketed since 1995 for the treatment of severe pain and is available in > 50 countries

1. Gilron et al., NEJM 2005

US diabetic neuropathy trial indicated potential added benefit

Co-administration of the two drugs already exists in practice

Anecdotal evidence suggests oxycodone and GBT may have additive efficacy

Pre-clinical data indicates an additive benefit of GBT with opioids

GBT plus opioid has been shown to provide effective pain relief at lower doses of each agent1

GBT / Opioid Combinations

Overview

OxyContin® tablets and gabapentin (GBT) – effectiveness in neuropathic pain

OXY3204 – a clinical review of OxyContin® tablets/GBT in combination

OXY3204

A double-blind, randomized, parallel group study to compare the efficacy, safety and tolerability of prolonged-release oxycodone taken in combination with GBT, versus placebo with GBT, for treatment of moderate to severe neuropathic pain in patients with diabetes mellitus

Study Objectives

Primary endpoint

Secondary endpoint

To evaluate the analgesic efficacy of OxyContin® tablets in combination with

GBT versus GBT alone

Comparison of both study arms with respect to:

Use of escape medication

Sleep disturbance/ sleep quality

Patients’ global assessment of pain

Study Design

Double-blind, randomized, parallel group

Patients randomized to receive oxycodone or placebo (1:1) whilst continuing prescribed GBT

All patients received OxyContin® tablets 5 mg at study initiation – titrated stepwise to optimize analgesia

Assessment Phase = for up to 12 weeks

Outcome visit after 30 days

Study Design

Screening5–14 days

Baseline visitn = 406

Randomisationn = 338

Placebo/GBT n = 169

Oxycodone/GBT n = 169

Week 12Completion visit

Outcome visit

30 days

12 weeks*

* 7 Visits at Weeks 1, 2, 3, 4, 6, 8, 12

Entry Criteria

Three month history of neuropathic pain due to diabetic neuropathy

Stable diabetes – HbA1c no greater than 11%

Max. Tolerated Dose (MTD) GBT for at least 1 month

Moderate-to-severe pain still evident despite GBT MTD

BS-11 of ≥ 5 at screening

No usage of long acting opioid ≤ 1 month of screening

No previous oxycodone/GBT combination exposure

No long-term opioid exposure

Concomitant Medication

The following were permitted:

NSAIDS and tricyclic antidepressants Only if initiated >3 weeks prior to screening and continued at stable

frequency and dose

Aspirin for cardiovascular indication (max. 300mg/day)

Any other medication not excluded by study exclusion criteria

Patient Characteristics

OxyContin®/GBT Placebo/GBT

Age (years) 59.710.2 60.69.9

Gender

Female

Male38%

62%

33%

67%

48

36

16

4339

16

0

10

20

30

40

50

60

<1200 mg/day 1200-1800mg/day

>1800 mg/day

Do

se o

f G

BT

pat

ien

ts r

ecei

ved

(%

)

Dose of GBT (mg/day)

Optimal GBT dose

Countries, Sites, Patients

Country No. of sites No. of patients screened No. of patients randomised

Australia 3 4 3

Austria 3 18 14

Belgium 3 8 8

Czech Republic 8 84 78

Denmark 3 26 20

France 1 4 3

Germany 13 61 52

Netherlands 3 24 18

Norway 2 11 10

Spain 8 35 28

Sweden 3 11 5

Switzerland 2 1 0

UK 18 119 99

Totals 70 406 338

N.B. 6 and 4 patients receiving oxycodone/GBT and GBT alone, respectively were excluded post-randomisation

Patient Disposition

Adverse events n = 9 (24%)Subject’s choice n = 6 (16%)

Administrative n = 2 (5%)Lack of therapeutic effect n = 20 (54%)

Adverse events n = 27 (64%)Subject’s choice n = 9 (21%)

Administrative n = 0 (0%)Lack of therapeutic effect n = 6 (14%)

Patients enrolled n = 406 Screen failures n = 68

Patients randomized n = 338

Placebo n = 169 OxyContin® n = 169

Completed Studyn = 128 (78%)

Withdrawnn = 37 (22%)Not analyzed

n = 4 (2%)

Completed studyn = 121 (74%)

Withdrawnn = 42 (26%)Not analyzed

n = 6 (4%)

Data Sets Analysed

Efficacy

Full analysis population – i.e. all patients who received at least one dose of study drug and had at least one primary efficacy measurement post-randomisation (n = 328)

Primary efficacy analysis i.e. Change in BS-11 Pain Scores

Safety

All patients receiving at least one dose of study medication and for whom one post-dose safety observation was obtained (n = 335)

Extent of Exposure

Approximately 60% of patients in both treatment groups remained on 20 mg b.i.d. study medication (OxyContin® tablets or placebo) per day

Results

Primary Result:

A statistically significant (p = 0.007) result in favour of the addition of oxycodone to GBT therapy

Clinically relevant reduction in pain scores for OxyContin® tablets/GBT vs. GBT alone

Primary Efficacy variable: Change in BS-11 pain scores

0

1

2

3

1 2 3 4 5 6 7

Cha

nge

in B

S-1

1 pa

in s

core

Study period

OxyContin®/GBTPlacebo/GBT

Change From Baseline in Mean Bs-11 Pain Scores

OxyContin®/GBT combination demonstrates significant overall treatment effect compared with Placebo/GBT p = 0.007

Secondary Efficacy ResultsEscape Medication Use

Patients in the OxyContin®/GBT group required statistically significantly fewer tablets of escape medication a day (p < 0.03) than GBT alone

00.5

11.5

22.5

33.5

44.5

5

0 1 2 3 4 5 6

Mea

n es

cape

med

icat

ion

(no.

of t

able

ts)

Study period

OxyContin®/GBT

Placebo/GBT

Secondary Efficacy ResultsSleep Disturbance

Patients in the OxyContin®/GBT group recorded statistically significantly fewer nights disturbed sleep (p < 0.05) than GBT alone

0

1

2

3

4

0 1 2 3 4 5 6 7

Med

ian

num

ber

of

nigh

ts d

istu

rbed

sle

ep

Study period

OxyContin®/GBT

Placebo/GBT

Sleep disturbance measured over previous 7 nights to measurement

Secondary Efficacy ResultsGlobal Assessment Of Pain Relief

Patients receiving OxyContin®/GBT had significantly better pain relief than GBT alone (p = 0.003)

* Patients who completed the study

56

74

60

4147

40

0

10

20

30

40

50

60

70

80OxyContin®/GBT n = 121*

Placebo/GBT n = 128*

Pe

rce

nta

ge

of

pa

tien

ts (

%)

Good/ very goodpain relief

Better/much betterthan pre-study

medication

Good/very goodoverall treatment

of pain

Exploratory Functional Efficacy ResultsPain Intensity/Score

Brief pain inventory (BPI) scores: oxycodone/GBT more effective than GBT alone

Mean pain intensity and mean pain interference (p < 0.001)

McGill pain questionnaire (short form): OxyContin® tablets/GBT more effective than GBT alone

Total pain intensity score (p < 0.001) Total sensory pain score (p < 0.001) Total affective pain score (p < 0.001)

VAS pain score for “pain last week” was statistically significantly lower (p = 0.001) for oxycodone/GBT combination

Present pain intensity was statistically significantly lower (p = 0.002) compared with study initiation

Mobility a greater percentage of OxyContin®/GBT patients demonstrated an improvement in mobility than GBT

alone (18% vs. 11%)

Self care both groups demonstrated a slight improvement in self care

Usual activities by the end of the study, more patients in both study groups were able to carry out their usual activities in the OxyContin® /GBT group, fewer patients remained unable to perform their usual activities

compared with GBT alone

Pain/discomfort at study end, 15% OxyContin® /GBT patients reported a reduction or absence of pain pain or

discomfort compared with only 7% of patients on GBT alone

Anxiety/depression by study end, the percentage of patients reporting they were not anxious or depressed increased by

18% in the OxyContin® /GBT group compared with an increase of only 10% with GBT

Patient resource utilisation very few patients in either group used additional health care resources between visits

Exploratory Functional Efficacy Results EuroQoL EQ-5D

Safety

Overall, treatment-emergent adverse events (AEs) were more frequently reported in patients in the OxyContin®/GBT group (88%) compared to patients receiving GBT (71%)

The most frequently reported AEs in the OxyContin® /GBT group were recognised opiate/induced AEs:

constipation (27%) nausea (26%) vomiting (10%) fatigue (18%) dizziness (15%) headache (10%) somnolence (22%)

SAEs were experienced by a comparable number in each group (oxycodone/GBT n = 19; Placebo/GBT n = 18)

There was one non-treatment-related death in the OxyContin®/GBT group (MI)

Safety

The majority of the treatment-emergent AEs were mild or moderate Patients receiving OxyContin®/GBT experienced more AEs associated with

opioids versus GBT alone (constipation and nausea)

AEs designated to be related to study treatment were all opiate-related (constipation, nausea, fatigue, dizziness and somnolence)

AEs were not exacerbated by the addition of OxyContin® tablets to GBT therapy

Conclusions

This study provides the first evidence that the addition of prolonged-release oxycodone to GBT therapy can improve outcomes for patients with diabetic neuropathy

OxyContin® plus GBT statistically and clinically significantly reduces patient pain scores

The difference between OxyContin®/GBT and GBT alone is statistically significant

Secondary and exploratory efficacy variables confirm the beneficial effect of OxyContin®/GBT for patients with diabetic neuropathy

Importantly, AEs were not exacerbated by the addition of OxyContin® tablets to GBT therapy

Thank you