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Overview

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.

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Overview

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  1. Overview Oxycodone and GBT – effectiveness in neuropathic pain OXY3204 – a clinical review of oxycodone/GBT in combination

  2. 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

  3. Oxycodone – in Neuropathic Pain Opioids have proven efficacy in neuropathic pain1 Opioids are recommended first-line therapy for neuropathic pain2 Oxycodone provides significant reductions in global pain scores in PHN3 Oxycodone Oxycodone significantly reduces pain in diateticneuropathy 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

  4. 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

  5. Overview Oxycodone and GBT – effectiveness in neuropathic pain OXY3204 – a clinical review of oxycodone/GBT in combination

  6. 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

  7. Comparison of both study arms with respect to: Use of escape medication Sleep disturbance/ sleep quality Patients’ global assessment of pain Study Objectives Primary endpoint To evaluate the analgesic efficacy of oxycodone in combination with GBT versus GBT alone Secondary endpoint

  8. 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

  9. Randomisation n = 338 12 weeks* Placebo/GBT n = 169 30 days Screening 5–14 days Outcome visit Oxycodone/GBT n = 169 Week 12 Completion visit Baseline visit n = 406 * 7 Visits at Weeks 1, 2, 3, 4, 6, 8, 12 Study Design

  10. 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

  11. 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

  12. Patient Characteristics Dose of GBT patients received (%) Dose of GBT (mg/day)

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

  14. Patients enrolled n = 406 Screen failures n = 68 Patients randomized n = 338 Placebo n = 169 Study drug n = 169 Completed Study n = 128 (78%) Withdrawn n = 37 (22%) Completed study n = 121 (74%) Withdrawn n = 42 (26%) 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%) Patient Disposition

  15. 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)

  16. Extent of Exposure • Approximately 60% of patients in both treatment groups remained on 20 mg study medication (oxycodone or placebo) per day

  17. 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

  18. Oxycodone/GBT Placebo/GBT Change in BS-11 pain score Study period Change From Baseline in Mean Bs-11 Pain Scores Oxycodone/GBT combination demonstrates significant overall treatment effect compared with Placebo/GBT p = 0.007

  19. Patients in the oxycodone/GBT group required statistically significantly fewer tablets of escape medication a day (p < 0.03) than GBT alone Oxycodone/GBT Placebo/GBT Mean escape medication (no. of tablets) Study period Secondary Efficacy ResultsEscape Medication Use

  20. Patients in the oxycodone/GBT group recorded statistically significantly fewer nights disturbed sleep (p < 0.05) than GBT alone Oxycodone/GBT Placebo/GBT Median number of nights disturbed sleep Study period Sleep disturbance measured over previous 7 nights to measurement Secondary Efficacy ResultsSleep Disturbance

  21. Patients receiving oxycodone/GBT had significantly better pain relief than GBT alone (p < 0.001) Oxycodone/GBT n = 121* Placebo/GBT n = 128* Percentage of patients (%) Good/ very good pain relief Better/much better than pre-study medication Good/very good overall treatment of pain * Patients who completed the study Secondary Efficacy ResultsGlobal Assessment Of Pain Relief

  22. Exploratory 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): 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

  23. 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

  24. 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)

  25. 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

  26. 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 • 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

  27. Thank you

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