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Abstracts (774) A multi-center, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of lacosamide (200, 400, and 600mg/day) in subjects with painful distal diabetic neuropathy P Kenney, J Simpson, B Koch; S SP768 Study Group, Schwarz Biosciences GmbH, Monheim, Germany Lacosamide (SPM 927) is being investigated as a possible anticonvulsant drug with potential for reducing diabetic neuropathic pain. In a previous pilot trial in subjects with moderate to severe painful diabetic neuropathy, lacosamide administered at 400mg/day for 4 weeks demonstrated a statistically significant reduction in pain as compared to placebo. In order to confirm these results, the efficacy and safety of lacosamide at doses of 200, 400, and 600mg/day were investigated in this double-blind, placebo-controlled, multi-center trial. Subjects with distal diabetic neuropathy ranging in duration from 6 months to 5 years were randomized to receive placebo, 200mg/day, 400mg/day, or 600mg/ day lacosamide in a 1:2:2:2 ratio, respectively. After a 2-week run-in, subjects entered a 6-week titration in which subjects titrated to their assigned dose in 100mg/day weekly increments then entered 12-weeks maintenance. No dose adjustments were allowed during the trial. The primary variable was change in average daily pain score from the baseline week to the last 4 weeks of the maintenance phase based on a 0-10 point Likert scale. Secondary variables included assessment of pain at each clinic visit using a 100mm visual analog scale (VAS), assessments of pain interference with subjects⬘ sleep and activity, quality of life, and global impression of change in pain (PGIC). Adverse events were assessed and recorded throughout the trial. A total of 468 subjects (266 male and 202 female) were randomized at 79 sites in the US and received at least one dose of trial medication. Sixty-seven percent (67%) of subjects were ⬍ 65 and 33% were ⱖ 65 years of age. Efficacy results for each treatment group are presented in the poster. Based on preliminary safety information, the most frequently reported adverse events were dizziness, headache, nausea, tremor, and diarrhea. Supported by grants from Schwarz Biosciences, Inc.
S45 (776) Refer to Oral Paper Session 312 (777) Pregabalin for painful diabetic peripheral neuropathy and postherpetic neuralgia: Onset and duration of analgesia in combined analyses of clinical studies R Portenoy, U Sharma, E Durso-de Cruz, J Young, T Griesing; Pfizer Global Pharmaceuticals, Pfizer Inc, New York, NY Numerous studies have demonstrated that pregabalin is effective in diverse types of neuropathic pain. These studies have assessed analgesic onset and duration of effect, relevant concerns in practice. We describe time to onset and duration of analgesia during studies of pregabalin for peripheral neuropathic pain. Data from 7 placebo-controlled RCTs (5-13 weeks long; 300 or 600 mg/d for DPN; 150, 300, or 600 mg/d for PHN; pregabalin, N⫽940; placebo, N⫽603) and 4 open-label (OL) extension trials (2 years in duration; flexible dosing; N⫽444 with dose data and N⫽251 with pain data) were evaluated in secondary combined analyses. Time of onset was defined by the first day on which 0-10 numeric daily pain scores were significantly lower than placebo on 2 consecutive days. Long-term outcomes included change in pregabalin dosages and corresponding pain levels (0-100 mm visual analogue scale). Onset of analgesia occurred on treatment day 1 or 2 in 9 of 11 study arms that had demonstrated significant efficacy at endpoint. In these 9 treatment arms, treatment effect on the first confirmed response day ranged from ⫺0.70 (P⫽.004) to ⫺1.40 (P⬍.001) in DPN and from ⫺0.45 (P⫽.036) to ⫺0.66 (P⫽.004) in PHN patients. Among patients in the OL trials, pain remained consistent from the first quarter (29.1⫾21.9) to 2-year follow-up (28.3⫾25.2), and there were no clinically meaningful variations in mean dosage over this period (Q1⫽361, 2-year [Q8] follow-up⫽375 mg/d; median 300 mg/d). Pregabalin’s long-term AE profile in these OL extension trials was similar to that reported in short-term RCTs. In shortterm RCTs, pregabalin showed rapid onset of effect, most commonly by Day 2 of treatment. In long-term OL trials, patients’ pain levels remained consistent, without clinically meaningful dose variations, for a period of 2 years.
(775) Duloxetine in the long-term management of diabetic peripheral neuropathic pain - results from three clinical trials
(778) RN624 (Anti-NGF) reduces pain and improves function in subjects with moderate to severe pain from osteoarthritis of the knee
J Raskin, F Wang, Y Pritchett, T Smith, A Chappell, D D’Souza, S Iyengar, J Wernicke; Eli Lilly and Company, Indianapolis, IN The safety of duloxetine 60 mg twice daily (BID) for up to 52 weeks was assessed, and duloxetine was compared with routine care in the management of diabetic peripheral neuropathic pain (DPNP). Results were pooled from three studies in which patients who completed a randomized, double-blind, placebo-controlled acute therapy period (12 to 13 weeks) were randomly reassigned in a 2:1 ratio to duloxetine 60 mg BID (N⫽580) or routine care (N⫽287) for 52 weeks. Routine care consisted primarily of acetylsalicylic acid, gabapentin, and paracetamol. Thirteen [4.5%] routine care- and 56 [9.7%] duloxetine-treated patients discontinued due to adverse events and 10 (1.2%) patients discontinued due to death (5 [1.7%] routine care-treated, 5 [0.9%] duloxetine-treated). Serious adverse events reported by ⬎1% of routine care-treated patients were myocardial infarction (2.4%), pneumonia (2.1%), congestive cardiac failure (1.7%), cerebrovascular accident (1.4%), and cellulitis (1%), and by ⬎1% of duloxetine-treated patients was myocardial infarction (1.6%). The treatment-emergent adverse events reported by ⬎5% of routine-care treated patients were nausea, fatigue, dizziness, headache, somnolence, nasopharyngitis, pain in extremity, peripheral edema, vomiting and arthralgia, and by ⬎5% of duloxetine-treated patients were nausea, fatigue, dizziness, headache, somnolence, nasopharyngitis, hyperhidrosis and diarrhea. Statistically significant therapy group differences were observed in fasting glucose (mean change [mmol/L]: ⫺0.64 [routine-care], 0.67 [duloxetine]), HbA1c (mean change: 0.002 [routine-care], 0.005 [duloxetine]), high density lipoprotein cholesterol (mean change [mmol/L]: ⫺0.078 [routine-care], ⫺0.014 [duloxetine]), diastolic blood pressure (mean change [mm Hg]: ⫺0.15 [routine-care], 1.38 [duloxetine]), and pulse (mean change [beats/min]: ⫺1.29 [routinecare], 1.52 [duloxetine]). Duloxetine did not appear to adversely affect eye or nerve function. These studies show that duloxetine is safe for use in long-term management of DPNP.
F Hefti, M Mokhtarani, M Gray, C Zhao, C Chan; Rinat Neuroscience, South San Francisco, CA New therapies are needed for patients with chronic moderate-to-severe pain from Osteoarthritis (OA) that is inadequately controlled by NSAIDs without the toxicities associated with opiates. RN624 is a humanized monoclonal antibody against nerve growth factor (NGF), a modulator of nociceptor function. This randomized, placebo-controlled, double-blind study examined the safety and efficacy of 2 doses of RN624 compared to placebo. 79 subjects (27 in 100ug/kg RN624, 26 in 300ug/kg RN624 and 26 in placebo) with chronic knee OA pain received a single dose of study drug and were followed through Day 181. Subjects in all treatment groups were comparable in terms of age, gender and baseline VAS (0-100 scale). Subjects recorded 4-times a day knee pain, daily walking pain, daily rescue medication use, and completed the WOMAC™ at time points throughout the study. Although the protocol-defined endpoint of summed pain intensity difference (SPID) for days 2-14 showed a modest decrease in the 100ug/kg RN624 group, it did not reach statistical significance from placebo. However post-hoc analysis of mean change from baseline for daily walking pain showed a statistically significant difference between both RN624 doses compared to placebo during days 2-56 post-dosing; the reduction was most evident during days 21-56. The WOMAC function subscale also showed significant improvement in the 100ug/kg RN624 group during days 28-56. No SAEs or discontinuations due to aes were reported. Overall more aes were reported in the first 28 days in the combined RN624 group as compared to placebo, with the majority reported in the nervous and musculoskeletal systems. Single infusion of RN624 produced a reduction in both walking in and overall pain due to OA of the knee. With careful monitoring of aes, RN624 may be an alternative therapy for the treatment of chronic moderate to severe pain from OA.
S45 (776) Refer to Oral Paper Session 312 (777) Pregabalin for painful diabetic peripheral neuropathy and postherpetic neuralgia: Onset and duration of analgesia in combined analyses of clinical studies R Portenoy, U Sharma, E Durso-de Cruz, J Young, T Griesing; Pfizer Global Pharmaceuticals, Pfizer Inc, New York, NY Numerous studies have demonstrated that pregabalin is effective in diverse types of neuropathic pain. These studies have assessed analgesic onset and duration of effect, relevant concerns in practice. We describe time to onset and duration of analgesia during studies of pregabalin for peripheral neuropathic pain. Data from 7 placebo-controlled RCTs (5-13 weeks long; 300 or 600 mg/d for DPN; 150, 300, or 600 mg/d for PHN; pregabalin, N⫽940; placebo, N⫽603) and 4 open-label (OL) extension trials (2 years in duration; flexible dosing; N⫽444 with dose data and N⫽251 with pain data) were evaluated in secondary combined analyses. Time of onset was defined by the first day on which 0-10 numeric daily pain scores were significantly lower than placebo on 2 consecutive days. Long-term outcomes included change in pregabalin dosages and corresponding pain levels (0-100 mm visual analogue scale). Onset of analgesia occurred on treatment day 1 or 2 in 9 of 11 study arms that had demonstrated significant efficacy at endpoint. In these 9 treatment arms, treatment effect on the first confirmed response day ranged from ⫺0.70 (P⫽.004) to ⫺1.40 (P⬍.001) in DPN and from ⫺0.45 (P⫽.036) to ⫺0.66 (P⫽.004) in PHN patients. Among patients in the OL trials, pain remained consistent from the first quarter (29.1⫾21.9) to 2-year follow-up (28.3⫾25.2), and there were no clinically meaningful variations in mean dosage over this period (Q1⫽361, 2-year [Q8] follow-up⫽375 mg/d; median 300 mg/d). Pregabalin’s long-term AE profile in these OL extension trials was similar to that reported in short-term RCTs. In shortterm RCTs, pregabalin showed rapid onset of effect, most commonly by Day 2 of treatment. In long-term OL trials, patients’ pain levels remained consistent, without clinically meaningful dose variations, for a period of 2 years.
(775) Duloxetine in the long-term management of diabetic peripheral neuropathic pain - results from three clinical trials
(778) RN624 (Anti-NGF) reduces pain and improves function in subjects with moderate to severe pain from osteoarthritis of the knee
J Raskin, F Wang, Y Pritchett, T Smith, A Chappell, D D’Souza, S Iyengar, J Wernicke; Eli Lilly and Company, Indianapolis, IN The safety of duloxetine 60 mg twice daily (BID) for up to 52 weeks was assessed, and duloxetine was compared with routine care in the management of diabetic peripheral neuropathic pain (DPNP). Results were pooled from three studies in which patients who completed a randomized, double-blind, placebo-controlled acute therapy period (12 to 13 weeks) were randomly reassigned in a 2:1 ratio to duloxetine 60 mg BID (N⫽580) or routine care (N⫽287) for 52 weeks. Routine care consisted primarily of acetylsalicylic acid, gabapentin, and paracetamol. Thirteen [4.5%] routine care- and 56 [9.7%] duloxetine-treated patients discontinued due to adverse events and 10 (1.2%) patients discontinued due to death (5 [1.7%] routine care-treated, 5 [0.9%] duloxetine-treated). Serious adverse events reported by ⬎1% of routine care-treated patients were myocardial infarction (2.4%), pneumonia (2.1%), congestive cardiac failure (1.7%), cerebrovascular accident (1.4%), and cellulitis (1%), and by ⬎1% of duloxetine-treated patients was myocardial infarction (1.6%). The treatment-emergent adverse events reported by ⬎5% of routine-care treated patients were nausea, fatigue, dizziness, headache, somnolence, nasopharyngitis, pain in extremity, peripheral edema, vomiting and arthralgia, and by ⬎5% of duloxetine-treated patients were nausea, fatigue, dizziness, headache, somnolence, nasopharyngitis, hyperhidrosis and diarrhea. Statistically significant therapy group differences were observed in fasting glucose (mean change [mmol/L]: ⫺0.64 [routine-care], 0.67 [duloxetine]), HbA1c (mean change: 0.002 [routine-care], 0.005 [duloxetine]), high density lipoprotein cholesterol (mean change [mmol/L]: ⫺0.078 [routine-care], ⫺0.014 [duloxetine]), diastolic blood pressure (mean change [mm Hg]: ⫺0.15 [routine-care], 1.38 [duloxetine]), and pulse (mean change [beats/min]: ⫺1.29 [routinecare], 1.52 [duloxetine]). Duloxetine did not appear to adversely affect eye or nerve function. These studies show that duloxetine is safe for use in long-term management of DPNP.
F Hefti, M Mokhtarani, M Gray, C Zhao, C Chan; Rinat Neuroscience, South San Francisco, CA New therapies are needed for patients with chronic moderate-to-severe pain from Osteoarthritis (OA) that is inadequately controlled by NSAIDs without the toxicities associated with opiates. RN624 is a humanized monoclonal antibody against nerve growth factor (NGF), a modulator of nociceptor function. This randomized, placebo-controlled, double-blind study examined the safety and efficacy of 2 doses of RN624 compared to placebo. 79 subjects (27 in 100ug/kg RN624, 26 in 300ug/kg RN624 and 26 in placebo) with chronic knee OA pain received a single dose of study drug and were followed through Day 181. Subjects in all treatment groups were comparable in terms of age, gender and baseline VAS (0-100 scale). Subjects recorded 4-times a day knee pain, daily walking pain, daily rescue medication use, and completed the WOMAC™ at time points throughout the study. Although the protocol-defined endpoint of summed pain intensity difference (SPID) for days 2-14 showed a modest decrease in the 100ug/kg RN624 group, it did not reach statistical significance from placebo. However post-hoc analysis of mean change from baseline for daily walking pain showed a statistically significant difference between both RN624 doses compared to placebo during days 2-56 post-dosing; the reduction was most evident during days 21-56. The WOMAC function subscale also showed significant improvement in the 100ug/kg RN624 group during days 28-56. No SAEs or discontinuations due to aes were reported. Overall more aes were reported in the first 28 days in the combined RN624 group as compared to placebo, with the majority reported in the nervous and musculoskeletal systems. Single infusion of RN624 produced a reduction in both walking in and overall pain due to OA of the knee. With careful monitoring of aes, RN624 may be an alternative therapy for the treatment of chronic moderate to severe pain from OA.