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Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy.

ABSTRACT: Introduction:Inflammatory cell recruitment, which is potentially mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor type 2 (CCR2) system and by C-C chemokine receptor type 5 (CCR5) activity, may play a role in the development and progression of diabetic nephropathy. PF-04634817 is a dual chemokine CCR2/5 receptor antagonist that is being developed for the treatment of diabetic nephropathy. Methods:We evaluated the efficacy of PF-04634817 compared with matching placebo for reduction of albuminuria after 12 weeks of treatment in subjects with type 2 diabetes who received standard of care (SOC; angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy), in a randomized, double-blind, placebo-controlled, parallel-group phase 2 study. Results:A total of 226 subjects who received SOC with baseline estimated glomerular filtration rates between 20 and 75 ml/min per 1.73 m2 and a baseline urinary albumin-to-creatinine ratio (UACR) of ?300 mg/g were randomly assigned 3:1 to receive PF-04634817 (150 or 200 mg orally, once daily) or placebo. The primary analysis was Bayesian, with an informative prior for placebo response (equivalent to including an additional 80 subjects in the placebo arm). We observed a placebo-adjusted reduction in UACR of 8.2% (ratio 0.918; 95% credible interval: 0.75-1.09) at week 12 in the PF-04634817 arm. PF-04634817 appeared to be safe and well-tolerated. Conclusion:Despite the good safety profile shown by PF-04634817, clinical development for this indication was discontinued in light of the modest efficacy observed.

SUBMITTER: Gale JD

PROVIDER: S-EPMC6224665 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy.

Gale Jeremy D JD Gilbert Steven S Blumenthal Samuel S Elliott Tom T Pergola Pablo E PE Goteti Kosalaram K Scheele Wim W Perros-Huguet Christelle C

Kidney international reports 20180803 6

<h4>Introduction</h4>Inflammatory cell recruitment, which is potentially mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor type 2 (CCR2) system and by C-C chemokine receptor type 5 (CCR5) activity, may play a role in the development and progression of diabetic nephropathy. PF-04634817 is a dual chemokine CCR2/5 receptor antagonist that is being developed for the treatment of diabetic nephropathy.<h4>Methods</h4>We evaluated the efficacy of PF-04634817 compared with matchi ...[more]

PMID: 30450458

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Project description:Background and objectivesAlbuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits.Design, setting, participants, & measurementsThis study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements.ResultsIncreasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone.ConclusionsIncreasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Dataset Information

Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy.

Publications

Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy.

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