title: CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study.
abstract: OBJECTIVE
  Macrophage recruitment through C-C motif chemokine receptor-2 (CCR2) into adipose tissue is believed to play a role in the development of insulin resistance and type 2 diabetes mellitus (T2DM). The objective of this Phase 2 proof-of-concept study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-41443532, an orally bioavailable CCR2 antagonist, in patients with T2DM.
  
  
  METHODS
  This was a 4-week, double-blind, placebo-controlled, randomized, multicenter study. A total of 89 patients were randomized to receive either 250- or 1000-mg of JNJ-41443532 twice daily, 30-mg of pioglitazone once daily (reference arm), or placebo. The primary endpoint was change from baseline in 23-h weighted mean glucose (WMG); secondary endpoints included change from baseline in fasting plasma glucose (FPG), insulin resistance (Homeostatic Model Assessment [HOMA-IR]), insulin secretion (HOMA-%B) and body weight.
  
  
  RESULTS
  Absorption of JNJ-41443532 into the systemic circulation occurred at a median tmax of 2 h, and the mean t½ was approximately 8 h for both doses; plasma systemic exposures increased slightly more than dose-proportionally. After 4 weeks, reductions in 23-h WMG and FPG were observed in all treatment groups compared with placebo and were significantly lower for 250-mg JNJ-41443532 and pioglitazone. HOMA-IR was lower for all treatment groups, but significantly lower only for pioglitazone. Conversely, HOMA-%B was increased for all groups, but significantly increased only for 250-mg JNJ-41443532. All groups, including placebo, had decreased body weight over time. There were no clinically significant findings during routine safety assessments and the incidence of treatment-emergent adverse events was similar across all groups.
  
  
  CONCLUSIONS
  Administration of JNJ-41443532 resulted in modest improvement in glycaemic parameters compared with placebo, and was generally well tolerated in patients with T2DM.
authors.affiliation: Department of Translational Medicine, Janssen Research & Development, Raritan, NJ, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Di Prospero
authors.forename: E
authors.initials: E
authors.lastname: Artis
authors.forename: P
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: D L
authors.initials: DL
authors.lastname: Johnson
authors.forename: N
authors.initials: N
authors.lastname: Vaccaro
authors.forename: L
authors.initials: L
authors.lastname: Xi
authors.forename: P
authors.initials: P
authors.lastname: Rothenberg
mesh_terms: D000328:Adult; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects*; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology; D037001:Directive Counseling; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005215:Fasting; D005260:Female; D006442:Glycated Hemoglobin / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D001384:Azetidines; D001549:Benzamides; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000077205:Pioglitazone; D054390:Receptors, CCR2; D045162:Thiazolidinediones; C515334:CCR2 protein, human; C000599181:JNJ-41443532; C517652:hemoglobin A1c protein, human
keywords: antidiabetic drug; clinical trial; insulin resistance; phase I-II study; randomized trial; type 2 diabetes