PMID- 24798870
OWN - NLM
STAT- MEDLINE
DCOM- 20150707
LR  - 20221207
IS  - 1463-1326 (Electronic)
IS  - 1462-8902 (Linking)
VI  - 16
IP  - 11
DP  - 2014 Nov
TI  - CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, 
      placebo-controlled study.
PG  - 1055-64
LID - 10.1111/dom.12309 [doi]
AB  - AIMS: 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 t(1/2) 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.
CI  - (c) 2014 John Wiley & Sons Ltd.
FAU - Di Prospero, N A
AU  - Di Prospero NA
AD  - Department of Translational Medicine, Janssen Research & Development, Raritan, 
      NJ, USA.
FAU - Artis, E
AU  - Artis E
FAU - Andrade-Gordon, P
AU  - Andrade-Gordon P
FAU - Johnson, D L
AU  - Johnson DL
FAU - Vaccaro, N
AU  - Vaccaro N
FAU - Xi, L
AU  - Xi L
FAU - Rothenberg, P
AU  - Rothenberg P
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20140525
PL  - England
TA  - Diabetes Obes Metab
JT  - Diabetes, obesity & metabolism
JID - 100883645
RN  - 0 (Azetidines)
RN  - 0 (Benzamides)
RN  - 0 (Blood Glucose)
RN  - 0 (CCR2 protein, human)
RN  - 0 (Glycated Hemoglobin A)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (JNJ-41443532)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Thiazolidinediones)
RN  - 0 (hemoglobin A1c protein, human)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
MH  - Adult
MH  - Azetidines/administration & dosage/pharmacokinetics/pharmacology
MH  - Benzamides/administration & dosage/pharmacokinetics/pharmacology
MH  - Blood Glucose/*drug effects
MH  - Body Mass Index
MH  - Diabetes Mellitus, Type 2/*drug therapy/epidemiology
MH  - Directive Counseling
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Fasting
MH  - Female
MH  - Glycated Hemoglobin/*drug effects
MH  - Humans
MH  - Hypoglycemic Agents/administration & dosage/*pharmacokinetics/pharmacology
MH  - Male
MH  - Middle Aged
MH  - Pioglitazone
MH  - Receptors, CCR2/*antagonists & inhibitors
MH  - Thiazolidinediones/administration & dosage/*pharmacokinetics/pharmacology
MH  - Treatment Outcome
MH  - United States/epidemiology
OTO - NOTNLM
OT  - antidiabetic drug
OT  - clinical trial
OT  - insulin resistance
OT  - phase I-II study
OT  - randomized trial
OT  - type 2 diabetes
EDAT- 2014/05/07 06:00
MHDA- 2015/07/08 06:00
CRDT- 2014/05/07 06:00
PHST- 2013/12/10 00:00 [received]
PHST- 2014/04/08 00:00 [revised]
PHST- 2014/04/28 00:00 [accepted]
PHST- 2014/05/07 06:00 [entrez]
PHST- 2014/05/07 06:00 [pubmed]
PHST- 2015/07/08 06:00 [medline]
AID - 10.1111/dom.12309 [doi]
PST - ppublish
SO  - Diabetes Obes Metab. 2014 Nov;16(11):1055-64. doi: 10.1111/dom.12309. Epub 2014 
      May 25.