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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