The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: A randomised trial

Abstract

Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care, including ACE inhibitors or ARBs.
In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2 diabetes aged 18-75 years with proteinuria (first morning void urinary albumin to creatinine ratio [UACR] 100-3000 mg/g), estimated glomerular filtration rate of 25 mL/min per 1·73 m(2) or higher, and taking stable antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratified based on baseline UACR and renal function (estimated glomerular filtration rate), and then randomly assigned (1:1:1) via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol amendment. The primary efficacy measure was change from baseline in UACR during 52 weeks in the modified intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. According to a prespecified analysis plan, we analysed the primary endpoint with one-sided statistical testing with calculation of upper 95% confidence limits of the differences between active and control. This trial is registered with ClinicalTrials.gov, number NCT01447147.
The study ran from Dec 7, 2011 (first patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the modified intention-to-treat population. UACR changes from baseline during 52 weeks were -2% for placebo (95% CI -11% to 9%), -18% for 5 mg CCX140-B (-26% to -8%), and -11% for 10 mg CCX140-B (-20% to -1%). We recorded a -16% difference between 5 mg CCX140-B and placebo (one-sided upper 95% confidence limit -5%; p=0·01) and a -10% difference between 10 mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0·08). Adverse events occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study.
Our data suggest that CCR2 inhibition with CCX140-B has renoprotective effects on top of current standard of care in patients with type 2 diabetes and nephropathy.
ChemoCentryx.
Copyright © 2015 Elsevier Ltd. All rights reserved.

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1
Articles
The eff ect of CCR2 inhibitor CCX140-B on residual
albuminuria in patients with type 2 diabetes and
nephropathy: a randomised trial
Dick de Zeeuw, Pirow Bekker, Elena Henkel, Christopher Hasslacher, Ioanna Gouni-Berthold, Heidrun Mehling, Antonia Potarca, Vladimir Tesar,
Hiddo J Lambers Heerspink, Thomas J Schall, for the CCX140-B Diabetic Nephropathy Study Group*
Summary
Background Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite
optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers
(ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C
chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care,
including ACE inhibitors or ARBs.
Methods In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research
centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2
diabetes aged 18–75 years with proteinuria (fi rst morning void urinary albumin to creatinine ratio [UACR]
100–3000 mg/g), estimated glomerular fi ltration rate of 25 mL/min per 1·73 m² or higher, and taking stable
antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratifi ed
based on baseline UACR and renal function (estimated glomerular fi ltration rate), and then randomly assigned (1:1:1)
via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg
CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol
amendment. The primary effi cacy measure was change from baseline in UACR during 52 weeks in the modifi ed
intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at
week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol
amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug.
According to a prespecifi ed analysis plan, we analysed the primary endpoint with one-sided statistical testing with
calculation of upper 95% confi dence limits of the diff erences between active and control. This trial is registered with
ClinicalTrials.gov, number NCT01447147.
Findings The study ran from Dec 7, 2011 (fi rst patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were
assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the
modifi ed intention-to-treat population. UACR changes from baseline during 52 weeks were –2% for placebo (95% CI
–11% to 9%), –18% for 5 mg CCX140-B (–26% to –8%), and –11% for 10 mg CCX140-B (–20% to –1%). We recorded
a –16% diff erence between 5 mg CCX140-B and placebo (one-sided upper 95% confi dence limit –5%; p=0·01) and a
–10% diff erence between 10 mg CCX140-B and placebo (upper 95% confi dence limit 2%; p=0·08). Adverse events
occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group
and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study.
Interpretation Our data suggest that CCR2 inhibition with CCX140-B has renoprotective eff ects on top of current
standard of care in patients with type 2 diabetes and nephropathy.
Funding ChemoCentryx.
Introduction
Patients with type 2 diabetes and proteinuria have a
high renal and cardiovascular morbidity and mortality.
Treatment of diabetic nephropathy, including with
angiotensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs), has been
e ective in reducing cardiovascular and renal risk.
These renal and cardiovascular protective properties of
renin-angiotensin-system (RAS) inhibitors have,
besides blood pressure lowering, been partly attributed
to their albuminuria lowering e ect.1–5 Despite the
success of RAS inhibitors, residual renal and
cardiovascular risk is very high6 and seems to be related
to the residual high albuminuria in these patients.1
Increasing the blockade of the RAS with ACE inhibitors,
ARBs, or renin-inhibition combinations has not been
successful in further reducing renal or cardiovascular
risk in this patient population.7,8
Novel treatment options that target other pathways
involved in the pathophysiology of diabetic nephropathy
are needed. Monocyte chemoattractant protein-1
(MCP-1), also called C-C chemokine ligand 2 (CCL2),
Lancet Diabetes Endocrinol 2015
Published Online
August 10, 2015
http://dx.doi.org/10.1016/
S2213-8587(15)00261-2
See Online/Comment
http://dx.doi.org/10.1016/
S2213-8587(15)00286-7
*Members listed in the appendix
Department of Clinical
Pharmacy and Pharmacology,
University of Groningen,
University Medical Center
Groningen (UMCG), Groningen,
the Netherlands
(Prof D de Zeeuw MD,
H J Lambers Heerspink PharmD);
ChemoCentryx, Mountain
View, CA, USA (P Bekker MBChB,
A Potarca MSc, T J Schall PhD);
Centre for Clinical Studies,
Technical University, Dresden,
Germany (E Henkel MD);
Diabetes Institute, Heidelberg,
Germany (C Hasslacher MD);
Center for Endocrinology,
Diabetes and Preventive
Medicine, University of
Cologne, Cologne, Germany
(I Gouni-Berthold MD); Charité
Experimental and Clinical
Research Centre, Berlin,
Germany (H Mehling MD); and
Department of Nephrology,
1st School of Medicine, Charles
University, Prague, Czech
Republic (Prof V Tesar MD)
Correspondence to:
Prof Dick de Zeeuw, Department
of Clinical Pharmacy and
Pharmacology, University
Medical Center Groningen,
9700 AD Groningen,
Netherlands
d.de.zeeuw@umcg.nl
See Online for appendix

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one of the ligands for C-C chemokine receptor type 2
(CCR2), has been implicated, not only in insulin
resistance,9,10 but also in progressive renal injury and
has been suggested to be a potential marker of renal
disease.11 MCP-1 promotes monocyte and macrophage
migration and activation.12 CCX140-B is a small-
molecule CCR2 antagonist that inhibits CCR2 and
blocks MCP-1-dependent monocyte activation and
chemotaxis. Data from preclinical studies suggested
that oral CCX140-B improved glycaemia and
albuminuria in a mouse model of diabetes.13 Our aim in
this study was to test the e cacy and safety of two doses
of CCX140-B on albuminuria in patients with type 2
diabetes and proteinuria.
Methods
Study design and participants
We did this randomised, double-blind, placebo-controlled
trial at 78 research centres in Belgium, Czech Republic,
Germany, Hungary, Poland, and the UK. The initial study
included a 12-week treatment period because toxicology
results were not available at the time to support longer
term dosing. After long-term toxicology had been
successfully completed, we amended the protocol to
extend dosing from 12 weeks to 52 weeks with a 4-week
follow-up visit after stopping treatment. This protocol
amendment specifi ed that for patients already enrolled,
only those who completed the initial 12-week study
visit within the previous 16 weeks were eligible for
continuation to 52 weeks. Therefore, 95 of 332 patients
were not eligible to continue to 52 weeks because they
had been o study treatment for more than 16 weeks at
the time the protocol amendment was approved.
Eligible patients were aged 18–75 years inclusive and
had type 2 diabetes with proteinuria (fi rst morning
urine albumin to creatinine ratio [UACR] 100–3000 mg/g),
a glomerular fi ltration rate based on the modifi cation of
diet in renal disease equation (estimated glomerular
fi ltration rate [eGFR]) of greater than or equal to
25 mL/min per 1·73 m², a baseline HbA1c between
6–10% (4·2–8·6 mmol/mol), and a fasting plasma
glucose of less than 270 mg/dL (15 mmol/L). Patients
were on stable diabetes treatment and ACE inhibitors
or ARBs at a recommended therapeutic dose for at least
8 weeks.
Patients were excluded if they had type 1 diabetes or
known non-diabetic renal disease; a BMI higher than
45·4 kg/m²; cardiac failure (class III or IV), history of
unstable angina, symptomatic coronary artery disease,
myocardial infarction or stroke within 12 weeks before
screening; haemoglobin less than 10 g/dL (6·18 mmol/L);
or evidence of hepatic disease (aspartate amino-
transferase, alanine transaminase, or bilirubin >two
times the upper limit of normal). Patients were also
excluded if they had poorly controlled blood pressure
(systolic blood pressure >155 mm Hg or diastolic blood
pressure >95 mm Hg). Additional exclusion criteria
were use of bardoxolone, atrasentan, or other endothelin
antagonist within 8 weeks before screening; chronic
(>7 days continuously) non-steroidal anti-infl ammatory
drug treatment within 2 weeks before screening, or any
infection requiring antibiotic treatment within 4 weeks
before screening. The appendix contains the full list of
inclusion and exclusion criteria.
The trial was done in accordance with the Declaration
of Helsinki and Good Clinical Practice guidelines. Ethics
committees and institutional review boards approved the
research protocol. All patients gave written informed
consent before starting the trial.
Randomisation and masking
After the lead-in period, patients were stratifi ed based
on baseline UACR (100–300 mg/g, 301–800 mg/g, and
801–3000 mg/g) and baseline eGFR (25–59 mL/min per
1·73 m² and ≥60 mL/min per 1·73 m²), and then randomly
assigned (1:1:1) to receive oral placebo, CCX140-B 5 mg, or
CCX140-B 10 mg once a day for 52 weeks according to a
non-centre-specifi c randomi sation scheme. Stratifi cation
Research in context
Evidence before this study
We searched PubMed on May 4, 2015, and again on July 24,
2015, with the following search terms: “CCR2” AND “clinical
trial”, “CCR2” AND “diabetes”, and “CCR2” AND “diabetic
nephropathy”. This did not reveal any previous clinical trials
with any CCR2 drug in diabetic nephropathy. Before this clinical
trial, no other studies had been published for drugs targeting
the chemokine receptor CCR2 in patients with diabetic
nephropathy. One phase 2 study has been published with
CCX140-B in patients with type 2 diabetes. Patients in that
study did not have renal disease.
Added value of this study
To the best of our knowledge, the results from our trial provide
the fi rst evidence that CCR2 inhibition lowers albuminuria in
patients with type 2 diabetes on standard-of-care treatment,
with no major side-eff ects. These eff ects are achieved through
interference with a novel pathway compared with existing
treatments.
Implications of all the available evidence
Albuminuria lowering is surrogate evidence for renal
protection. The results of this trial showing that CCX140-B
lowers albuminuria should be translated into hard evidence in
follow-up studies that test whether CCX140-B also limits
progression to end-stage renal disease. If this is the case,
CCX140-B might have the potential to alter and attenuate the
relentless decline of renal function in patients with type 2
diabetes and proteinuria and thereby the need for expensive
renal replacement treatment.

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3
and randomisation was undertaken centrally via an
interactive web response system. The system used a
minimisation algorithm14 to maintain balance among the
three treatment groups with respect to the three baseline
UACR ranges, the two baseline eGFR ranges, and study
centre. Patients and all study personnel (except the safety
monitoring committee) were masked to treatment
allocation. CCX140-B is the sodium salt of CCX140. All
study drugs were in identical capsules, and supplied in
identical bottles labelled appropriately so as to maintain
the allocation masking.
Procedures
Patients who were randomised collected fi rst morning
void urine on 3 separate days at baseline and week 52,
and single measurements at weeks 2, 4, 8, 12, 16, 20, 28,
36, 44, and 56 for assessment of UACR. Urine albumin was
measured by a nephelometric assay and creatinine was
measured by a kinetic colorimetric assay in a central
laboratory (Medpace Reference Laboratory, Leuven,
Belgium). Serum creatinine, phosphorus, blood urea
nitrogen, and urinary MCP-1 to creatinine ratio were
measured at baseline and 2, 4, 8, 12, 16, 20, 28, 36, 44, 52,
and 56 weeks. Serum creatinine was used to calculate
eGFR with the modifi cation of diet in renal disease
equation:
eGFR=175 × (serum creatinine, mg/dL) ¹·¹ × (age, years)
·²³ × (0·742 if female) × (1·212 if black).
We measured HbA1c, fasting plasma glucose, and
homoeostatic model assessment of insulin resistance
(HOMA-IR) at baseline and 4, 8, 12, 20, 28, 36, 44, 52, and
56 weeks. HOMA-IR was calculated with the following
equation: fasting plasma glucose (mg/dL) × fasting
insulin (U/mL)/405. Plasma MCP-1 concentrations were
measured at baseline and weeks 12, 28, 52, and 56.
CCX140 plasma concentrations were measured at each
study visit using high-performance liquid chromatography
with tandem mass spectrometric detection (lower limit of
detection 1 ng/mL).
Safety was monitored at baseline and 2, 4, 8, 12, 20, 28,
36, 44, 52, and 56 weeks by assessing adverse events and
laboratory data. Reported adverse events were recorded
during the trial and analysed with a standard coding
dictionary (MedDRA, version 12.0) to classify adverse
event terms. Serious adverse events were defi ned as any
adverse event that resulted in death, was immediately life
threatening, required hospital admission, resulted in
persistent or substantial disability or incapacity, was a
birth defect, or was an important event that might heavily
jeopardise the patient or might have required intervention
to prevent any of the above.
We assessed patient compliance with taking study drug
based on returned capsule counts at each study visit as
well as plasma CCX140 concentrations measured over
the course of the trial.
Outcomes
The primary e cacy endpoint for the study was change
from baseline in UACR at 52 weeks. Because the treatment
period in the original protocol was 12 weeks, change
from baseline in UACR over 12 weeks was also analysed.
Secondary endpoints included change from baseline in
eGFR and HbA1c at 52 weeks. Other endpoints included
change from baseline in blood urea nitrogen, serum
phosphorus, fasting plasma glucose, fasting plasma
insulin, HOMA-IR, urinary MCP-1 to creatinine ratio
and plasma MCP-1 at week 52, and the plasma
concentration of CCX140 over the course of the study.
Statistical analysis
The planned sample size was at least 135 patients, 45 in
each group. However, the protocol made provision for an
enrolment target of 270 patients, 90 in each group, with
the anticipation that the trial dosing period might be
extended with potential loss of patients while the protocol
amendment was processed. Assuming a standard
deviation of 0·85, a sample size of 45 per group was
estimated to provide 80% power to detect a mean
between-group di erence in UACR change of 0·51,
corresponding to a 40% between-group di erence. A
sample size of 90 per group was estimated to provide
80% power to detect a mean between-group di erence in
UACR change of 0·36, corresponding to a 30% between-
group di erence.
We did e cacy analyses on the modifi ed intention-to-
treat population, which consisted of all patients with
uninterrupted dosing between the 12 week and 16 week
study visits. We excluded from the modifi ed intention-
to-treat population patients who stopped dosing at
week 12, either permanently, under the original protocol,
or temporarily, due to delay in protocol amendment
approval. The statistical analysis plan was revised
during the study to refl ect the dosing period extension
and change in primary endpoint (from week 12 to
week 52). We did safety analyses on all randomly
assigned patients who received at least one dose of study
drug. Analyses were based on comparisons between
placebo and CCX140-B groups as assigned by
randomisation, irrespective of whether patients followed
through the protocol or were fully compliant with the
protocol procedures.
The primary analysis was a mixed e ects model,
repeated measures (MMRM) analysis of change from
baseline to each post-baseline measurement of log UACR
using SAS (version 9.1). The model included treatment,
visit, and treatment-by-visit interaction as factors, and
baseline log UACR, eGFR, HbA1c, and mean arterial
pressure as covariates. UACR was log-transformed before
entering the data in the MMRM analysis to alleviate the
skewness of the data.
Visits were included as repeated measure units
from the same patients. To allow generality for the
covariance structure for the repeated measures, the

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variance-covariance matrix was assumed to be
unstructured—ie, purely data dependent. In this MMRM
model, all patients and all datapoints were included. No
patients were excluded because of missing data and no
imputation was done for missing data. We estimated the
treatment group di erence at week 52 with the simple
contrast and the overall between-group di erence over
the course of the study with the main e ects (contrast)
with the missing at random assumption. We compared
the contrast between each drug dose group and the
placebo group at week 52 with a prespecifi ed one-sided
signifi cance level of 0·05; treatment di erences at other
timepoints were also analysed.
The between-group geometric mean change (%) was
derived by 100*(exp [least squares mean change]–1), and
the same transformation was applied to the 95% confi dence
limits to obtain an approximate upper 95% confi dence
limit for the geometric mean change (%). The rationale for
one-sided testing for UACR was that in this phase 2 clinical
trial, the main goal was to test whether CCX140-B treatment
can reduce albuminuria. This was not a pivotal clinical trial,
in which a two-sided test would be more appropriate. We
used similar statistical models to assess treatment group
di erences in other e cacy and safety variables, such as
eGFR, HbA1c, and urinary MCP-1 to creatinine ratio. We
calculated two-sided 95% confi dence intervals for eGFR.
Figure 1: Trial profi le
UACR=urinary albumin to creatinine ratio. eGFR=estimated glomerular fi ltration rate. FPG=fasting plasma glucose. *Patient withdrawn because of discovery of
leukaemia medical history in the past (protocol deviation). †Patient withdrawn because of myocardial infarction and depression leading to diffi culty for patient to
comply with the protocol. ‡Patient withdrawn because of diagnosis of rectal cancer and diffi culty for patient to comply with the protocol.
883 patients screened
332 patients randomly assigned to treatment
111 assigned to placebo
(safety population)
110 assigned to 5 mg CCX140-B
(safety population)
111 assigned to 10 mg CCX140-B
(safety population)
10 discontinued
4 withdrew consent
5 adverse events (confusion,
balance disorder, heart valve
incompetence, prostate
cancer, myocardial infarction)
1 investigator decision*
6 discontinued
2 withdrew consent
4 adverse events (staphylococcal
bacteraemia, depression,
constipation, rash)
5 discontinued
3 withdrew consent
2 adverse events (anxiety,
diarrhoea)
106 completed 12 weeks 104 completed 12 weeks 101 completed 12 weeks
31 not eligible due to off study
drug for >16 weeks
3 withdrew consent
32 not eligible due to off study drug
for >16 weeks
4 withdrew consent
32 not eligible due to off study drug
for >16 weeks
64 uninterrupted dosing 63 uninterrupted dosing 65 uninterrupted dosing
59 completed 56 weeks 61 completed 56 weeks 62 completed 56 weeks
3 discontinued
2 withdrew consent
1 adverse event (atrial
fibrillation)
2 discontinued
1 relocation
1 investigator decision‡
5 discontinued
3 withdrew consent
1 adverse event (pneumonia)
1 investigator decision†
70 continued after 12 weeks 69 continued after 12 weeks 70 continued after 12 weeks
5 interrupted dosing6 interrupted dosing 6 interrupted dosing
551 ineligible
340 due to UAC R too low
39 due to HbA1c too low
26 due to UACR too high
24 due to eGFR too low
22 due to FPG too high
19 due to HbA1c too high
15 due to consent withdrawn
66 due to other inclusion or exclusion criteria

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5
A sensitivity analysis of change from baseline in log
UACR was done by an ANCOVA model with treatment as
a factor and baseline eGFR, HbA1c, and mean arterial
pressure as covariates, and last observation carried
forward imputation for missing data. Concomitant
drugs including RAS inhibitors, diuretics, β blockers,
calcium channel blockers, glucose-lowering drugs, and
lipid-modifying drugs were summarised by treatment
group.
The study was registered with ClinicalTrials.gov,
number NCT01447147.
Role of the funding source
The study was overseen by an advisory committee,
including members from the funder. The advisory
committee oversaw the design of the study, the conduct
of the trial, and the management and analysis of all data.
The funder was involved in the design of the study, in the
collection and analysis of the data, and in writing the
report. All authors had access to study results, and the
lead author takes responsibility for the accuracy and
completeness of the data reported. The lead author and
the advisory committee had the fi nal decision to submit
the publication.
Results
The study ran from Dec 7, 2011 (fi rst patient enrolled)
until Aug 4, 2014. We screened 883 patients of whom we
enrolled 332. 111 patients were assigned to placebo,
110 to CCX140-B 5 mg, and 111 to CCX140-B 10 mg.
209 patients continued after the 12-week period of whom
192 had uninterrupted treatment after week 12 (modifi ed
intention-to-treat population). 182 of the 192 patients
completed 56 weeks (fi gure 1).
Baseline demographics, clinical and biochemical
characteristics, and concomitant drugs were similar
between the three groups (table 1 and appendix). Apparent
slight baseline imbalances in average baseline plasma
MCP-1 concentrations are explained by one outlier value
each in the 5 mg and 10 mg CCX140-B group.
Repeated measures analysis showed a signifi cant least
squares mean change from baseline in albuminuria for
CCX140-B 5 mg (fi gure 2): –18% (95% CI –26% to
–8%; p=0·0004) compared with placebo –2% (95% CI
–11% to 9%; p=0·72) during 52 weeks; the di erence
between 5 mg CCX140-B and placebo was –16%
(one-sided 95% upper confi dence limit –5%; p=0·01).
The 10 mg dose showed a –11% (95% CI –20% to –1%;
p=0·02) least squares mean change from baseline
during 52 weeks; –10% (upper 95% confi dence limit 2%)
compared with placebo (p=0·08). Figure 2 also shows
the albuminuria changes in time. Geometric mean UACR
of 363 mg/g (95% CI 287–460) at baseline in the 5 mg
group was reduced to 276 mg/g (199–383) (–24% change;
p=0·0007) after 12 weeks of treatment, and remained
stable, ending at 296 mg/g (217–404) (–20% change;
p=0·03) at 52 weeks. The 10 mg dose of CCX140-B
showed a similar profi le of response in the fi rst 12 weeks,
–20% (95% CI –32 to –7) reduction compared with
baseline (p=0·005), but the e ect dissipated during the
subsequent weeks. For patients receiving placebo,
Placebo
(n=64)
5 mg CCX140-B
(n=63)
10 mg CCX140-B
(n=65)
Demographic characteristics
Age (years) 62·4 (7·6) 62·5 (8·0) 62·3 (7·9)
Women 15 (23%) 16 (25%) 14 (22%)
Ethnic origin
White 61 (95%) 62 (98%) 64 (98%)
Black 0 0 1 (2%)
Asian 3 (5%) 0 0
Pacifi c Islander 0 1 (2%) 0
Clinical characteristics
Weight (kg) 94·8 (18·6) 96·7 (13·7) 99·4 (17·4)
Known duration of diabetes (years) 14·9 (7·2) 15·0 (8·1) 16·3 (9·0)
Systolic blood pressure (mm Hg) 136·4 (15·2) 135·6 (14·5) 138·7 (14·2)
Diastolic blood pressure (mm Hg) 79·1 (9·2) 76·0 (9·0) 79·0 (8·4)
Serum albumin (g/L) 44·4 (3·2) 45·3 (3·7) 42·5 (8·0)
Serum creatinine (μmol/L)* 111·4 (42·5) 112·3 (42·0) 117·6 (47·3)
eGFR (mL/min per 1·73 m²) 64·2 (26·1) 62·4 (24·2) 61·1 (25·1)
Haemoglobin (g/L) 136·3 (13·4) 139·4 (16·2) 136·2 (15·9)
HbA1c (%) 7·7 (1·0) 7·5 (0·9) 7·8 (1·1)
Total cholesterol (mmol/L) 4·77 (1·05) 4·51 (1·12) 4·36 (1·00)
Serum potassium (mmol/L) 4·57 (0·48) 4·71 (0·50) 4·62 (0·49)
UACR (mg/g)† 440 (351–550) 363 (287–460) 438 (345–557)
Fasting plasma glucose (mmol/L) 8·79 (2·35) 9·46 (2·20) 9·46 (2·65)
Fasting plasma insulin (pmol/L) 210·4 (401·3) 150·7 (139·9) 181·3 (209·7)
HOMA-IR 13·0 (31·7) 9·5 (10·2) 11·9 (18·5)
Blood urea nitrogen (mmol/L) 8·50 (3·38) 9·25 (4·06) 9·03 (3·56)
Plasma MCP-1 (pg/mL) 218·3 (69·3) 283·0 (532·8) 229·3 (81·6)
Urine MCP-1 to creatinine ratio (pg/mg) 216·5 (310·5) 163·7 (120·4) 210·7 (165·9)
Drug treatments‡
Antihypertensives
ACE inhibitors 41 (64%) 45 (71%) 36 (55%)
Angiotensin receptor blockers 23 (36%) 18 (29%) 25 (39%)
ACE inhibitors plus angiotensin receptor
blockers
0 0 3 (5%)
β-blocking agents 29 (45%) 30 (48%) 29 (45%)
Dihydropyridine derivatives (calcium channel
blockers)
34 (53%) 34 (54%) 31 (48%)
Thiazides 10 (16%) 10 (16%) 11 (17%)
Drugs used in diabetes
Insulin and insulin analogues 33 (52%) 23 (37%) 29 (45%)
Biguanides (metformin) 36 (56%) 40 (64%) 33 (51%)
Sulphonamides, urea derivatives 18 (28%) 21 (33%) 15 (23%)
HMG CoA reductase inhibitors 40 (63%) 43 (68%) 40 (62%)
Data are mean (SD) or n (%) unless stated otherwise. The appendix shows characteristics of all randomised patients.
ACE=angiotensin-converting enzyme. eGFR=estimated glomerular fi ltration rate. UACR=urine albumin to urine
creatinine ratio. MCP-1=monocyte chemoattractant protein-1. HOMA-IR=homoeostatic model assessment of insulin
resistance. HMG CoA=3-hydroxy-3-methyl-glutaryl-CoA. *To convert to mg/dL, divide by 88·4. †Geometric mean and
95% CI. ‡Baseline drug treatments were summarised by selected Anatomical Therapeutic Chemical (ATC) classifi cation
system codes using WHO dictionary (version 9.1).
Table 1: Baseline characteristics of patients in the modifi ed intention-to-treat population

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baseline UACR showed no signifi cant change over time.
4 weeks after drug discontinuation, geometric mean
UACR remained at similar levels as the in-trial results for
all groups (fi gure 2). Results from a sensitivity analysis
using an ANCOVA model were consistent with the
MMRM analysis (appendix). The UACR response to
CCX140-B showed no interactions with the di erent
baseline parameters except for HbA1c, although the latter
with no consistent pattern (appendix). Because many
patients who completed the original 12-week protocol
were ineligible to participate in the 52-week protocol, we
assessed the results for all randomly assigned patients to
assess whether the results were consistent. The
albuminuria change at week 12 was –18% (upper 95%
confi dence limit –7%; p=0·006) for the 5 mg CCX140-B
and –4% (upper 95% confi dence limit 9%; p=0·29) for
the 10 mg group compared with placebo. The baseline
characteristics of all randomly assigned patients versus
the 52-week population showed no meaningful
di erences (appendix), suggesting that the 52-week
population was representative of the randomised
population.
Changes in eGFR, HbA1c, fasting plasma insulin,
HOMA-IR, serum phosphorus, blood urea nitrogen,
blood pressure, and urinary MCP-1 in participants who
received CCX140-B were not signifi cant compared with
those who received placebo (table 2 and appendix). There
was a greater change in fasting plasma glucose in
the 5 mg CCX140-B group compared with placebo
(–1·12 mmol/L, upper 95% confi dence limit –0·24;
Figure 2: Primary endpoint
Urinary albumin to creatinine ratio change in percent geo metric mean from baseline to 56 weeks for patients receiving placebo, CCX140-B 5 mg, or CCX140-B 10 mg.
Least-squares means change (±95% CIs) in urinary albumin to creatinine ratio (integral response) are plotted on the right hand side of the fi gure and represent the
primary endpoint. *p=0·01 for CCX140-B compared with placebo.
Number at risk
Placebo
5 mg CCX140-B
10 mg CCX140-B
0 4 8 12 16 20 24 28 32 36 40 44 48 52
*
Recovery
Least-squares
mean
56
64
63
65
64
63
63
64
63
65
64
62
62
62
60
59
62
58
57
62
59
57
59
59
56
59
57
57
58
58
56
58
58
52
58
58
57
Time (weeks)
–30
–25
–20
–15
–10
–5
0
5
10
15
Albuminuria change from baseline (%)
Placebo
5 mg CCX140-B
10 mg CCX140-B
Placebo 5 mg CCX140-B 10 mg CCX140-B
n Least-squares mean
(95% CI)
n Least-squares mean
(95% CI)
p value vs
placebo
n Least-squares mean
(95% CI)
p value vs
placebo
eGFR (mL/min/1·73 m²) 57 –2·6 (–4·6 to –0·6) 58 –2·4 (–4·4 to –0·4) 0·88 52 –3·8 (–5·9 to –1·8) 0·39
HbA1c (%) 58 0·12 (–0·08 to 0·33) 57 0·16 (–0·05 to 0·36) 0·58 52 –0·08 (–0·29 to 0·13) 0·08
Fasting plasma glucose (mmol/L) 58 0·38 (–0·36 to 1·11) 56 –0·74 (–1·49 to 0·01) 0·01 52 –0·37 (–1·13 to 0·39) 0·08
Fasting plasma insulin (pmol/L) 58 –48·9 (–106·6 to 8·8) 56 –14·5 (–73·0 to 44·1) 0·40 52 –0·1 (–59·7 to 59·5) 0·24
HOMA-IR 58 –2·14 (–6·59 to 2·31) 56 –1·37 (–5·88 to 3·14) 0·59 52 –1·20 (–5·77 to 3·38) 0·61
Phosphorus (mmol/L) 57 0·06 (0·03 to 0·10) 58 0·03 (–0·01 to 0·07) 0·20 52 0·03 (–0·01 to 0·07) 0·26
Blood urea nitrogen (mmol/L) 57 0·34 (–0·27 to 0·96) 58 0·49 (–0·13 to 1·11) 0·74 52 –0·07 (–0·71 to 0·57) 0·35
Plasma MCP-1 (pg/mL) 58 42·3 (4·4 to 80·3) 58 69·7 (32·1 to 107·3) 0·31 52 111·0 (69·6 to 152·5) 0·01
Urine MCP-1 to creatinine ratio (%) 57 26 (3 to 55) 57 46 (19 to 79) 0·84 47 29 (3 to 61) 0·55
Plasma CCX140 at week 52 (ng/mL), mean (SD) .. .. 57 1265 (379) NA 55 2299 (1057) NA
Data are least-squares mean (95% CI) unless otherwise noted. HOMA-IR=homoeostasis model assessment of insulin resistance; MCP-1=monocyte chemoattractant protein-1; NA=not applicable. Plasma CCX140
concentrations were not measured in the placebo group. p values are from the mixed model of repeated measures analysis including treatment, visit, treatment-by-visit interaction as factors, and baseline log
UACR, eGFR, HbA1c, and mean arterial pressure as covariates.
Table 2: Summary of change from baseline to week 52 by treatment group for secondary and other study endpoints in the modifi ed intention-to-treat population

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7
p=0·01). The average plasma concentration of CCX140
was roughly twice as high in the 10 mg CCX140-B group
compared with the 5 mg CCX140-B group, and remained
stable over the course of the study (appendix). The
average plasma MCP-1 concentration rose signifi cantly
in the 10 mg CCX140-B group but not in the other two
groups (table 2 and fi gure 3A). The UACR response
(baseline to week 52) seemed to be attenuated in the
presence of higher rise in plasma levels of MCP-1 upon
treatment (fi gure 3B).
The study drug was generally well tolerated (table 3).
Adverse events were consistent with the age and
underlying medical conditions of the patient population.
We noted that serious adverse events occurred in a
similar proportion of participants in the placebo and
5 mg CCX140-B groups (13 [11·7%] in the placebo group
and 13 [11·8%] in the 5 mg CCX140-B group). The 10 mg
CCX140-B group had a higher incidence of serious
adverse events: 25 (22·5%). Two serious adverse events
in the placebo group, and one each in the 5 mg and
10 mg CCX140-B groups, were reported to possibly be
related to the study drug: complete atrioventricular block
and myocardial infarction; Staphylococcal bacteraemia
after tooth extraction (5 mg CCX140-B) and subcutaneous
abscess (10 mg CCX140-B). Two patients died during the
course of the study, neither deemed drug related by the
investigators (one due to stroke in the 5 mg CCX140-B
group and one due to myocardial infarction in the 10 mg
CCX140-B group). None of the patients had a renal event:
no confi rmed doubling of serum creatinine over the
course of the study, none underwent dialysis, and none
had an eGFR of less than 15 mL/min per 1·73 m².
Patient compliance with taking study drug was high:
108 (97%) of 111 in the placebo group, 108 (98%) of 110 in
the 5 mg CCX140-B group, and 108 (97%) of 111 patients
in the 10 mg CCX140-B group took more than 90% of
their prescribed study drug. Compliance was further
substantiated by the plasma CCX140 concentration
measurements over the course of the study. Six (3%) of
221 patients, three in each of the CCX140-B groups, had
evidence of non-compliance based on plasma CCX140
concentrations.
Discussion
In patients with type 2 diabetes with proteinuria who
were on a therapeutic dose of ACE inhibitor or ARB, a
dose of 5 mg CCX140-B lowered albuminuria by 18%
overall versus 2% with placebo during the course of the
study without major side-e ects. The magnitude of this
e ect is deemed clinically meaningful and could translate
into further renal benefi t with long-term treatment.
Recently the focus of renoprotective treatments has
switched from targeting haemodynamic pathways to
infl ammatory pathways. Further inhibition of the RAS
seems to cause increased side-e ects that might counteract
the benefi cial e ects of reducing classical risk factors like
glucose, blood pressure, and albuminuria. Targeting other
pathways might be a better option for enhanced renal
protection in advanced type 2 diabetes. The chemokine
receptor 2 pathway seems interesting in view of the fact
that this pathway has been associated with progressive
renal function loss,11 and that inhibition of CCR2 a ords
renal protection in experimental models of renal disease.13
This is the fi rst study describing the e ect of CCR2
inhibition on renal risk parameters such as albuminuria,
in patients with type 2 diabetes and nephropathy.
The exact mechanism of the renoprotective e ect
of CCR2 inhibition is unknown. Several possibilities
have been discussed11,13,15,16 including blocking renal
macrophage infi ltration, infl ammation, oxidative stress,
improving podocyte number and function, and
interaction with the RAS. Our trial was designed to
Figure 3: MCP-1 response and the relation with UACR
(A) Least squares mean (95% CI) change in plasma MCP-1 levels in the placebo, 5 mg CCX140-B group, and 10 mg CCX140-B group at week 52. (B) Geometric mean
(95% CI) albuminuria change versus the geometric mean change (95% CI) in MCP-1 change (in tertiles) from baseline to week 52 for the 5 mg CCX140-B group and
10 mg CCX140-B group combined (p for trend [continuous]=0·03). Median plasma concentrations of MCP-1 tertiles at week 52 are 257 pg/mL in the lower tertile,
279 pg/mL in the middle tertile, and 353 pg/mL in the upper tertile. UACR=urinary albumin to creatinine ratio. *p=0·01 for CCX140-B compared with placebo.
Placebo
5 mg CCX140-B 10 mg CCX140-B
0
20
40
60
80
100
120
140
160
180
Change in plasma MCP-1 concentration (pg/mL)
A
–20 0 20 40 60 80 100 120 140
–60
–40
–20
0
20
*
40
Albuminuria change (%)
MCP-1 change (%)
B

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inform the design and study population for a potential
phase 3 trial. It was not designed to explore the
mechanism by which CCX140-B lowers albuminuria,
and thus does not further detail the mechanism of
CCR2 inhibition in renal protection. We selected
CCX140-B doses of 5 mg and 10 mg once a day because
both result in plasma concentrations that block
CCR2-mediated cell migration at about 90% or greater,13
and both doses were found to be safe and well tolerated
in an earlier study in patients with type 2 diabetes.17
Placebo
(n=111)
5 mg
CCX140-B
(n=110)
10 mg
CCX140-B
(n=111)
Patients with any adverse event 81 (73%) 71 (65%) 68 (61%)
Patients with any serious
adverse event
13 (12%) 13 (12%) 25 (23%)
Patients with adverse events
leading to discontinuation of
study drug
3 (3%) 6 (6%) 6 (5%)
Renal events
Doubling of serum creatinine 0 0 0
eGFR <15 mL/min per
1·73 m²
00 0
Dialysis or transplantation 0 0 0
Death 0 1 (<1%) 1 (<1%)
All patients with serious adverse events per system organ class
Infections and infestations 4 (4%) 4 (4%) 6 (5%)
Pneumonia 2 (2%) 1 (<1%) 1 (<1%)
Cellulitis 0 0 1 (<1%)
Gangrene 0 0 1 (<1%)
Lobar pneumonia 0 0 1 (<1%)
Localised infection 0 0 1 (<1%)
Lower respiratory infection 0 1 (<1%) 0
Respiratory tract infection 0 0 1 (<1%)
Septic shock 0 0 1 (<1%)
Staphylococcal
bacteraemia
0 1 (<1%) 0
Subcutaneous abscess 1 (<1%) 0 1 (<1%)
Urinary tract infection 0 1 (<1%) 0
Lung infection 1 (<1%) 0 0
Cardiac disorders 3 (3%) 2 (2%) 4 (4%)
Angina unstable 0 2 (2%) 1 (<1%)
Atrial fi brillation 0 0 1 (<1%)
Cardiac failure 1 (<1%) 0 1 (<1%)
Coronary artery stenosis 0 1 (<1%) 0
Myocardial infarction 1 (<1%) 0 1 (<1%)
Atrioventricular block
complete
1 (<1%) 0 0
Gastrointestinal disorders 2 (2%) 1 (<1%) 4 (4%)
Abdominal pain 0 0 1 (<1%)
Duodenal ulcer 0 0 1 (<1%)
Gastrointestinal
haemorrhage
0 0 1 (<1%)
Nausea 0 0 1 (<1%)
Refl ux oesophagitis 0 1 (<1%) 0
Constipation 1 (<1%) 0 0
Diarrhoea 1 (<1%) 0 0
Metabolism and nutrition
disorders
0 2 (2%) 2 (2%)
Hyperglycaemia 0 1 (<1%) 1 (<1%)
Diabetes mellitus 0 0 1 (<1%)
Hypoglycaemia 0 1 (<1%) 0
(Table 3 continues in next column)
Placebo
(n=111)
5 mg
CCX140-B
(n=110)
10 mg
CCX140-B
(n=111)
(Continued from previous column)
Neoplasms benign,
malignant and unspecifi ed
2 (2%) 1 (<1%) 3 (3%)
Renal cancer 0 0 2 (2%)
Prostate cancer 0 0 1 (<1%)
Rectal cancer stage IV 0 1 (<1%) 0
Bladder transitional cell
carcinoma
1 (<1%) 0 0
Meningioma 1 (<1%) 0 0
Nervous system disorders 1 (<1%) 2 (2%) 2 (2%)
Ischaemic stroke 0 1 (<1%) 1 (<1%)
Balance disorder 0 0 1 (<1%)
Cerebrovascular accident 0 1 (<1%) 0
Subarachnoidal
haemorrhage
0 0 1 (<1%)
Cerebral infarction 1 (<1%) 0 0
Vascular disorders 2 (2%) 1 (<1%) 2 (2%)
Deep vein thrombosis 0 0 1 (<1%)
Femoral arterial stenosis 0 0 1 (<1%)
Hypertension 0 1 (<1%) 0
Peripheral vascular disorder 1 (<1%) 0 0
Subclavian steal syndrome 1 (<1%) 0 0
Renal and urinary disorders 1 (<1%) 1 (<1%) 1 (<1%)
Renal failure acute 1 (<1%) 1 (<1%) 1 (<1%)
Respiratory, thoracic and
mediastinal disorders
1 (<1%) 1 (<1%) 1 (<1%)
Chronic obstructive
pulmonary disease
1 (<1%) 1 (<1%) 0
Pulmonary embolism 0 0 1 (<1%)
Skin and subcutaneous
tissue disorders
0 0 2 (2%)
Angioedema 0 0 1 (<1%)
Purpura senile 0 0 1 (<1%)
Eye disorders 0 0 1 (<1%)
Eye haemorrhage 0 0 1 (<1%)
Injury, poisoning, and
procedural complications
2 (2%) 0 1 (<1%)
Fall 0 0 1 (<1%)
Spinal compression
fracture
1 (<1%) 0 0
Tendon rupture 1 (<1%) 0 0
Musculoskeletal and
connective tissue disorders
1 (<1%) 0 0
Meniscal degeneration 1 (<1%) 0 0
Data are n (%). eGFR=estimated glomerular fi ltration rate.
Table 3: Adverse events in the safety population

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9
CCX140-B improves proteinuria and glycaemia in
mice13 and our study points to similar e ects in human
beings. Could the e ect on proteinuria and glycaemia be
related? In mice, the e ect on proteinuria was noted
earlier after treatment onset, and at lower doses of the
CCR2 inhibitor, than was the e ect on glycaemia.13 The
benefi cial e ect of CCR2 inhibition on glycaemic control
is thought to be related to a reduction in the macrophage
content in adipose tissue, leading to improved insulin
sensitivity.9,10 The e ect on proteinuria is probably caused
by other mechanisms, such as reduced infl ammation or
improved podocyte integrity.
An important fi nding was the apparent lack of a dose
response in our study. The 10 mg dose seemed to have
less albuminuria-lowering e ect than 5 mg CCX140-B.
The drug was adequately absorbed, as participants in the
10 mg CCX140-B group had twice the plasma drug levels
as the 5 mg dose. However, we also noted that
concentrations of an endogenous ligand for CCR2,
MCP-1 (also known as CCL2) rose with increasing dose
of the drug. Within each of the groups that received
CCX140-B, we noted that higher MCP-1 levels were
associated with less reduction in albuminuria, especially
in the 10 mg group.
We hypothesise that the increased concentrations of
MCP-1 compete with the drug. This is consistent with
reaching the plateau of the dose response with
10 CCX140-B mg at 12 weeks and attenuation of the
albuminuria-lowering e ect after week 12 in the 10 mg
CCX140-B group. Compliance as shown by the reported
taking of study drug was high and similar across groups.
Additionally, CCX140 plasma concentrations were
consistent across all study visits. The dropout rate in the
5 mg and 10 mg CCX140-B groups was similar. Therefore,
non-compliance with study drug or patient dropout were
unlikely to explain the attenuation of the drug’s e ect after
week 12 in the 10 mg group.
Our study design has limitations. In particular, the
study was amended from a 12-week study to a 52-week
study; not all patients enrolled in the 12-week study
could continue into the 52-week study because at the
crucial time of re-enrolment into the study extension,
the long-term toxicology data were not yet available.
This resulted in a loss of patients that had been exposed
to drug or placebo without interruption between
weeks 12 and 16. However, UACR results at week 12 for all
randomly assigned patients were consistent with the
results from patients with uninterrupted treatment
after week 12, suggesting that we did not selectively lose
patients.
What are the chances that 5 mg CCX140-B will be
renoprotective and delay hard renal endpoints? We noted
that changes in eGFR were not markedly di erent
between the placebo group and the 5 mg CCX140-B after
1 year. However, a di erence was not expected in view of
the the fact that the study was not statistically powered
for this endpoint. Moreover previous hard outcome trials
have shown renal protection in end stage renal disease
endpoints without marked changes in eGFR slopes
during 1 year.18 The fi nding that CCX140-B lowered
albuminuria by 16% compared with placebo, on top of
standard of care, could be an indicator of potential renal
protection. Findings of a recent meta-analysis showed
that all interventions that lower albuminuria by more
than 15% in the fi rst months of treatment are associated
with an improvement in hard renal outcomes compared
with standard of care.19 Whether this will hold true for
CCX140-B, which has a novel mechanism of action
compared with existing treatments, is unknown. The
current profi le of CCX140-B does not show any emerging
side-e ects such as hyperkalaemia or cardiovascular
events that could o set its benefi cial renoprotective
properties.
In conclusion, 5 mg CCX140-B once a day lowers
albuminuria in patients with type 2 diabetes and
proteinuria, on top of standard of care, and without any
marked side-e
ects. These results suggest that
CCX140-B is a promising candidate for further clinical
development to reduce the unmet need for treatments
for diabetic renal disease.
Contributors
PB and TJS designed the study with scientifi c advisers. PB and AP ran
the study with their teams. EH, CH, IG-B, HM, and VT enrolled patients
and critically reviewed the manuscript. DdZ, PB, and HJLH performed
the data analysis and statistical analysis. All authors interpreted the data.
DdZ wrote the draft of the report and all authors contributed to its
revisions. DdZ takes responsibility for the full report. The appendix lists
all investigators who enrolled patients in the trial.
Declaration of interests
DdZ is a consultant for and receives honoraria (to employer) from
AbbVie, Astellas, ChemoCentryx, Eli Lilly, Janssen, Fresenius,
Merck Darmstadt. PB, AP, and TJS are employees and shareholders of
ChemoCentryx, the funder of this study. IG-B has received research
grants from Bayer HealthCare; consultant, advisory board or lecture fees,
and travel expenses from Genzyme, MSD, Novartis, Novo Nordisk,
Pfi zer, Ipsen, Bristol-Myers Squibb, AstraZeneca, Aegereon, Amgen,
Sanofi , Otsuka, Lilly, Chiesi, and ChemoCentryx. EH, CH, and HM have
no declarations regarding potential confl ict of interest. VT obtained
lecture fees from Roche, Medonet, Baxter, Fresenius Medical Care,
B. Braun, and Amgen, and consulting fees from AbbVie, ChemoCentryx,
and Boehringer Ingelheim. He has served as a member of the Advisory
Board of AbbVie, Amgen, Fresenius Medical Care, and Baxter. HJLH
received a research grant from AstraZeneca (payment to employer) and
is a consultant for and receives honoraria (to employer) from AbbVie,
Astellas, Janssen, Reata Pharmaceuticals, and ZS-Pharma.
Acknowledgments
This study was funded by ChemoCentryx. We thank all study
coordinators, investigators, and patients for their valuable contribution.
We thank Chao Wang (Pharma Data Associates), Sharon Barker
(Medpace), and Tobias Kröpelin (University Medical Centre
Groningen), who helped with statistical analysis; and Israel Charo for a
critical review of the report.
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