title: A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain.
abstract: ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 microg BID, ABT-594 225 microg BID, or ABT-594 300 microg BID. Patients were titrated to a fixed-dose of ABT-594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT-594 treatment groups showed significantly greater decreases on the average diary-based 0-10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, -1.1; 150 microg BID, -1.9; 225 microg BID, -1.9; 300 microg BID, -2.0). The proportion of patients achieving at least a 50% improvement in the average diary-based PRS was greater in all three ABT-594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 microg BID, 46% for 225 microg BID, and 66% for 300 microg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.
authors.affiliation: UCSF Pain Clinical Research Center, University of California, San Francisco, CA, USA Abbott Laboratories, 200 Abbott Park Rd., Abbott Park, IL, USA University of Wisconsin, Madison, WI, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rowbotham
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Duan
authors.forename: James
authors.initials: J
authors.lastname: Thomas
authors.forename: Wolfram
authors.initials: W
authors.lastname: Nothaft
authors.forename: Misha-Miroslav
authors.initials: MM
authors.lastname: Backonja
mesh_terms: D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use*; D001384:Azetidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003627:Data Interpretation, Statistical; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012959:Socioeconomic Factors; D016896:Treatment Outcome
chemical_list: C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D018712:Analgesics, Non-Narcotic; D001384:Azetidines; D018722:Nicotinic Agonists; D011725:Pyridines