Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial Reportar como inadecuado




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Arthritis Research and Therapy

, 14:R11

First Online: 17 January 2012Received: 17 August 2011Revised: 13 December 2011Accepted: 17 January 2012

Abstract

IntroductionThe purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 CCR5 antagonist, is safe and effective in the treatment of active rheumatoid arthritis RA in patients on background methotrexate MTX.

MethodsThis phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics PK of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept POC component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily BID for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components.

ResultsSixteen patients were treated in the safety-PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients 38 maraviroc; 21 placebo had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc 23.7% and placebo 23.8% groups treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504. The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation 7.8%, nausea 5.2%, and fatigue 3.9%.

ConclusionsMaraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX.

Trial RegistrationClinicalTrials.gov: NCT00427934

AbbreviationsACRAmerican College of Rheumatology

ACR20American College of Rheumatology 20% improvement criteria

ACR50American College of Rheumatology 50% improvement criteria

ACR70American College of Rheumatology 70% improvement criteria

AEadverse event

AUCarea under the plasma concentration-time profile

AUC0-4area under the plasma concentration-time profile from time 0 to 4 hours postdose

BIDtwice daily

CCR1CC chemokine receptor type 1

CCR5human CC chemokine receptor 5

CIconfidence interval

Cmaxpeak plasma concentration

CRPC-reactive protein

DASdisease activity score

DAS28-4 CRPdisease activity score: 28-joint count: using C-reactive protein

DDIdrug-drug interaction

ECGelectrocardiogram

FASfull analysis set

IASinterim analysis set

MIPmacrophage inflammatory protein

MTXmethotrexate

PKpharmacokinetics

POCproof-of-concept

RArheumatoid arthritis

RANTESRegulated upon Activation: Normal T-cell Expressed: and Secreted

Tmaxtime to peak plasma concentration

ULNupper limit of normal range.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3685 contains supplementary material, which is available to authorized users.

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Autor: Dona L Fleishaker - Juan A Garcia Meijide - Andriy Petrov - Michael David Kohen - Xin Wang - Sujatha Menon - Thomas C S

Fuente: https://link.springer.com/







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