Transcript OXY3204 - epgonline.org

Overview
Oxycodone and GBT – effectiveness in neuropathic pain
OXY3204 – a clinical review of oxycodone/GBT in combination
GBT – in Neuropathic Pain
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
Gabapentin
26–38% patients receive maximal doses of GBT
but not full pain resolution1
1. Gilron et al., NEJM 2005
Oxycodone – in Neuropathic Pain
Opioids have proven efficacy in neuropathic pain1
Opioids are recommended first-line therapy for
neuropathic pain2
Oxycodone
Oxycodone provides significant reductions in global
pain scores in PHN3
Oxycodone significantly reduces pain in diatetic
neuropathy and improves QoL4
1. Ballantyne Oncologist. 2003; 2. Dworkin et al., Arch Neurol. 2003;
3. Watson et al., Neurology 1998; 4. Watson et al., Pain 2003
GBT / Opioid Combinations
GBT plus opioid has been shown to provide effective pain
relief at lower doses of each agent1
Pre-clinical data indicates an additive benefit of GBT
with opioids
Anecdotal evidence suggests oxycodone and GBT
may have additive efficacy
US diabetic neuropathy trial indicated potential added benefit
Co-administration of the two drugs already exists in practice
1. Gilron et al., NEJM 2005
Overview
Oxycodone and GBT – effectiveness in neuropathic pain
OXY3204 – a clinical review of oxycodone/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
oxycodone 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 oxycodone 5 mg at study initiation – titrated
stepwise to optimize analgesia
Assessment Phase = for up to 12 weeks
Outcome visit after 30 days
Study Design
Randomisation
n = 338
12 weeks*
Placebo/GBT n = 169
30 days
Screening
5–14 days
Oxycodone/GBT n = 169
Baseline visit
n = 406
* 7 Visits at Weeks 1, 2, 3, 4, 6, 8, 12
Outcome
visit
Week 12
Completion visit
Study Population
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
Dose of GBT patients received (%)
Patient Characteristics
60
50
48
43
40
36
39
30
20
16
16
10
0
<1200 mg/day
1200-1800
mg/day
>1800 mg/day
Dose of GBT (mg/day)
Age (years)
Gender
Female
Male
Oxycodone/GBT
Placebo/GBT
59.710.2
60.69.9
38%
33%
62%
67%
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
Patients enrolled n = 406
Screen failures n = 68
Patients randomized n = 338
Placebo n = 169
Completed Study
n = 128 (78%)
Withdrawn
n = 37 (22%)
Adverse events n = 9 (24%)
Subject’s choice n = 6 (16%)
Administrative n = 2 (5%)
Lack of therapeutic effect n = 20 (54%)
Study drug n = 169
Completed study
n = 121 (74%)
Withdrawn
n = 42 (26%)
Adverse events n = 27 (64%)
Subject’s choice n = 9 (21%)
Administrative n = 0 (0%)
Lack of therapeutic effect n = 6 (14%)
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 study medication (oxycodone or placebo) per day
Results
Primary Efficacy variable: Change in BS-11 pain scores
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 oxycodone/GBT
vs. GBT alone
Change From Baseline in Mean
Bs-11 Pain Scores
Change in BS-11 pain score
Oxycodone/GBT combination demonstrates significant overall treatment
effect compared with Placebo/GBT p = 0.007
5
Oxycodone/GBT
Placebo/GBT
4
3
2
1
0
1
2
3
4
Study period
5
6
7
Secondary Efficacy Results
Escape Medication Use
Mean escape medication
(no. of tablets)
Patients in the oxycodone/GBT group required statistically significantly fewer tablets of
escape medication a day (p < 0.03) than GBT alone
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Oxycodone/GBT
Placebo/GBT
0
1
2
3
Study period
4
5
6
Secondary Efficacy Results
Sleep Disturbance
Patients in the oxycodone/GBT group recorded statistically significantly fewer nights
disturbed sleep (p < 0.05) than GBT alone
Median number of
nights disturbed sleep
4
Oxycodone/GBT
Placebo/GBT
3
2
1
0
0
1
2
3
4
Study period
Sleep disturbance measured over previous 7 nights to measurement
5
6
7
Secondary Efficacy Results
Global Assessment Of Pain Relief
Patients receiving oxycodone/GBT had significantly better pain relief than
GBT alone (p < 0.001)
Oxycodone/GBT n = 121*
Percentage of patients (%)
80
Placebo/GBT n = 128*
74
70
60
60
56
47
50
40
40
31
30
20
10
0
Good/ very good
pain relief
* Patients who completed the study
Better/much better
than pre-study
medication
Good/very good
overall treatment
of pain
Exploratory Efficacy Results
Pain 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): oxycodone/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
Exploratory Efficacy Results
EuroQoL EQ-5D
Mobility

a greater percentage of oxycodone/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 oxycodone/GBT group, fewer patients remained unable to perform their usual activities
compared with GBT alone
Pain/discomfort

at study end, 15% Oxycodone/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 oxycodone/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
Safety
Overall, treatment-emergent adverse events (AEs) were more
frequently reported in patients in the oxycodone/GBT group (88%)
compared to patients receiving GBT (71%)
The most frequently reported AEs in the oxycodone/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 oxycodone/GBT
group (MI)
Safety
The majority of the treatment-emergent AEs were mild or moderate

Patients receiving oxycodone/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 oxycodone to GBT therapy
Conclusions
This study provides the first evidence that the addition of prolongedrelease oxycodone to GBT therapy can improve outcomes for patients
with diabetic neuropathy
Oxycodone plus GBT statistically and clinically significantly reduces
patient pain scores
The difference between oxycodone/GBT and GBT alone is statistically
significant
Secondary and exploratory efficacy variables confirm the beneficial
effect of oxycodone/GBT for patients with diabetic neuropathy
Importantly, AEs were not exacerbated by the addition of oxycodone
to GBT therapy
Thank you