SHQFFHVV LDEHWHVHWDEROLVP HVHDUFKUWLFOH Keywords Chemokine Receptor  CCR CCR antagonist MCP  Chemokine Chemokine receptor Type  diabetes Abbreviations AE Adverse Event AUC Area Under the Curve CCL Ch
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SHQFFHVV LDEHWHVHWDEROLVP HVHDUFKUWLFOH Keywords Chemokine Receptor CCR CCR antagonist MCP Chemokine Chemokine receptor Type diabetes Abbreviations AE Adverse Event AUC Area Under the Curve CCL Ch

MCP1 released by adipocytes attracts CCR2expressing monocytes into the adipose tissue where they di57492erentiate into macrophages leading to lowgrade in57493ammation that contributes to insulin resistance 4 Mice de57481cient for CCR2 have reduced m

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SHQFFHVV LDEHWHVHWDEROLVP HVHDUFKUWLFOH Keywords Chemokine Receptor CCR CCR antagonist MCP Chemokine Chemokine receptor Type diabetes Abbreviations AE Adverse Event AUC Area Under the Curve CCL Ch




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Presentation on theme: "SHQFFHVV LDEHWHVHWDEROLVP HVHDUFKUWLFOH Keywords Chemokine Receptor CCR CCR antagonist MCP Chemokine Chemokine receptor Type diabetes Abbreviations AE Adverse Event AUC Area Under the Curve CCL Ch"— Presentation transcript:


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2SHQ$FFHVV 'LDEHWHV0HWDEROLVP 5HVHDUFK$UWLFOH Keywords: Chemokine Receptor 2 (CCR2); CCR2 antagonist; MCP- 1; Chemokine; Chemokine receptor; Type 2 diabetes Abbreviations: AE: Adverse Event; AUC: Area Under the Curve; CCL2: Chemokine Ligand 2; CCR2: C-C Chemokine Receptor 2; DMC: Data Monitoring Committee; FPG: Fasting Plasma Glucose; HbA 1c : Hemoglobin A 1c ; HDL: High density lipoprotein; HOMA-IR: Homeostasis Assessment of Insulin Resistance; hsCRP: High Sensitivity C-Reactive Protein; LDL: Low Density Lipoprotein; MCP-1: Monocyte

Chemoattractant Protein-1; NEFA: Non-Esteried Fatty Acid; OGTT: Oral Glucose Tolerance Test; SAE: Serious Adverse Event; TC: Total Cholesterol Introduction Monocyte chemoattractant protein-1 (MCP-1) also named chemokine ligand 2 (CCL2), a potent chemoattractant for the C-C chemokine receptor 2 (CCR2)-expressing monocytes and macrophages [1,2], has been implicated in the pathogenesis of insulin resistance [3,4]. MCP-1, released by adipocytes, attracts CCR2-expressing monocytes into the adipose tissue where they dierentiate into macrophages, leading to low-grade

inammation that contributes to insulin resistance [4]. Mice decient for CCR2 have reduced macrophage numbers in adipose tissue and display signicantly improved metabolic parameters relative to wild-type counterparts [5]. Also, blocking CCR2 with the CCR2 antagonist propagermanium reduces adipose tissue macrophage inltration, insulin resistance, and glycemia in diet-induced obese C57Bl6 mice [6], and the CCR2 antagonist RS504393 improves insulin resistance, lipid metabolism, and nephropathy in db/db mice [7]. ese preclinical ndings provided the

basis for testing a CCR2 antagonist in patients with type 2 diabetes. CCX140-B is an orally-administered, specic CCR2 antagonist. is pilot Phase 2 clinical trial was conducted with the primary objective to evaluate the safety and tolerability of CCX140-B given once &RUUHVSRQGLQJDXWKRU 3LURZ%HNNHU&KHPR&HQWU\[,QF0DXGH$YHQXH

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&LWDWLRQ +DQHIHOG 6FKHOO *RXQL%HUWKROG 0HOLFKDU 9HVHOD HWDO 2UDOO\$GPLQLVWHUHG&KHPRNLQH5HFHSWRU&&5$QWDJRQLVW

&&;%LQ7\SH'LDEHWHV$3LORW'RXEOH%OLQG5DQGRPL]HG&OLQLFDO7ULDO-'LDEHWHV0HWDEGRL daily for 28 days in subjects with type 2 diabetes. Secondary objectives included the evaluation of the anti-glycemic eect of CCX140-B and the pharmacokinetic prole of CCX140-B in these subjects. Methods is was a randomized, double-blind, placebo- and

active- controlled parallel group clinical trial conducted at 32 study centers in Australia, Czech Republic, Germany, Hungary, and New Zealand from January 2010 to November 2010. e target enrollment was 140 subjects. Responsible ethics committees at all study centers provided approval of the trial before subject enrollment and the trial was conducted according to the principles of the Declaration of Helsinki as revised in 2000. Aer obtaining written informed consent, a total of 159 subjects with type 2 diabetes were recruited and randomly assigned, in a 1:2:1:1 ratio, to

receive placebo, 5 mg CCX140-B, 10 mg CCX140-B, or 30 mg pioglitazone once daily in 28 days, and then followed for a 28- day washout period without receiving study medication. e treatment duration was limited to 28 days, because, at the time of study launch, only 28-day toxicology data were available for CCX140-B to support dosing in humans. erefore, only 4-week treatment was allowed by ethics committees and regulatory authorities. An independent Data Monitoring Committee (DMC) reviewed unblinded safety data twice over the course of the trial. No interim analysis for

ecacy was performed. e study population included male and post-menopausal or surgically sterile female subjects, aged 18 to 70 years, inclusive, with type 2 diabetes. Subjects had a body mass index of at least 25 kg/m but less than 45 kg/m , HbA 1c of 6.5 to 10.0%, inclusive, fasting plasma glucose (FPG) of 135 to 270 mg/dL, inclusive, and were on a stable dose of metformin for at least 8 weeks prior to randomization (no minimum or maximum dose specied). All subjects were on background metformin treatment, because it was considered inappropriate to include subjects who

were not on any anti-diabetic treatment in this rst proof-of-concept clinical trial. Subjects on lipid-lowering agents were on a stable dose for at least 4 weeks prior to randomization, because one of the study objectives was to evaluate the potential eect of CCX140-B on plasma lipids, and changes in doses of lipid-lowering drugs prior to the dosing period could potentially be confounding. CCX140-B (the sodium salt of CCX140) was given as hard gelatin capsules containing 2.5 mg CCX140 each. Matching placebo capsules were given to protect the study blind. e subjects in

the placebo group received four placebo capsules daily, the 5 mg group received two 2.5 mg CCX140-B and two placebo capsules daily, and the 10 mg group received four 2.5 mg CCX140-B capsules daily. e active comparator group took one pioglitazone hydrochloride 30 mg tablet from commercial supply once daily in an open-label manner. e primary objective was safety assessment based on adverse event incidence. Other safety assessments included physical examination abnormalities, vital signs changes, and clinical laboratory parameter changes (including chemistry, hematology, and

urinalysis). Secondary ecacy parameters included change in FPG concentration and HbA 1c . Other measurements included oral glucose tolerance test (OGTT) with insulin, homeostasis assessment of insulin resistance (HOMA- IR), fasting plasma insulin, fasting plasma fructosamine, serum total adiponectin, plasma MCP-1, serum high sensitivity C-reactive protein (hsCRP), serum lipids including total cholesterol (TC), high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol, triglycerides (TGs), and non-esteried fatty acids (NEFAs). e

pre-specied primary time point of interest was day 29 (end of treatment). Plasma concentrations of CCX140 were measured in samples taken at all post-baseline stu dy visits (Days 8, 15, 22, 29, 36, 43, and 57). With the planned sample size of 56 and 28 subjects for the 5 mg and 10 mg CCX140-B groups, respectively, a dierence of approximately 14 and 17 mg/dL in fasting glucose between each of the active groups, respectively, and placebo could be detected with statistical power of at least 80%, assuming a type I error=0.025 and S.D. of change from baseline=20 mg/dL, to allow for

comparison of each of the two CCX140-B groups and placebo. It was estimated that approximately 10% of subjects would not complete the study through day 29. Eligible subjects were stratied based on MCP-1 polymorphism status (base pair: -2518, G vs. non-G) as well as gender. Subjects were then randomized in a 1:2:1:1 ratio to one of four treatment groups: placebo, CCX140-B 5 mg, CCX140-B 10 mg, or pioglitazone 30 mg once daily. erefore, twice as many subjects were randomized to the CCX140-B 5 mg group compared to the other treatment groups, because this dose was considered to

potentially be the minimally eective dose, based on preclinical results available at the time the trial was designed. e CCX140-B doses of 5 mg and 10 mg were chosen based on data from a diet-induced obese mouse model of diabetes, where blockade of CCR2 resulted in an anti-glycemic eect at plasma concentrations corresponding to anticipated plasma levels adjusted for relative potency of CCX140-B across species with 5 or 10 mg CCX140-B in humans. e pioglitazone dose of 30 mg was chosen because, according to the label, it was considered the appropriate starting dose

to treat patients with type 2 diabetes. Stratication and randomization were performed centrally via an interactive voice/web response system. A blocked randomization schedule was generated pre-study by a biostatistician who was otherwise not involved in the study. To conceal the allocation sequence, placebo and CCX140-B capsules and bottles were identical in appearance and subjects received two bottles of study medication on day 1 and day 15, and were asked to take 2 capsules from each bottle every morning, aer an overnight fast of at least 10 hours. e

placebo-controlled part of the study was double-blind. Blinding of the study was achieved by identical study medication bottle and capsule appearance, limited access to the randomization code, and blinding of ecacy data that would potentially have been unblinding, such as FPG results, unless required for safety monitoring. No inferential statistical analysis was planned or performed on safety data because of the exploratory nature and relatively small size of the trial. e main ecacy hypothesis was that at least one dose of CCX140-B would result in a statistically

signicant reduction in FPG compared to placebo at Study day 29. is hypothesis was tested using linear contrasts of an analysis of covariance model with treatment group as a factor and baseline FPG as a covariate. All statistical testing was 2-sided, and Dunnett’s adjustment was used to control the type I error rate at α=0.05. e primary ecacy analysis was performed in the Intent-to-Treat population. If the model was determined not to be appropriate due to non-normality of residuals, the Wilcoxon Rank Sum test was to be used to compare the CCX140-B dose

groups to the placebo group. e OGTT was conducted on day 1 (prior to the rst dose) and day 29 as follows: Aer an overnight fast of at least 10 hours, an oral dose of 75 g of glucose in 1 cup (240 mL) of water was given in the morning and was consumed within 5 minutes. Blood samples for plasma glucose and insulin measurements were taken at time 0 (just before the glucose was taken), and at 30, 60, 90, 120, and 180 minutes aer the glucose dos e. Areas under the curve (AUCs) were calculated
Page 3
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*RXQL%HUWKROG 0HOLFKDU 9HVHOD HWDO 2UDOO\$GPLQLVWHUHG&KHPRNLQH5HFHSWRU&&5$QWDJRQLVW &&;%LQ7\SH'LDEHWHV$3LORW'RXEOH%OLQG5DQGRPL]HG&OLQLFDO7ULDO-'LDEHWHV0HWDEGRL for each

subject’s glucose and insulin proles following the oral dose of glucose before treatment (Study day 1) and aer treatment (Study day 29). e changes in AUC across treatment groups were compared. e rest of the ecacy variables were analyzed in a similar manner as FPG, i.e., based on change from baseline, except for serum lipids for which percentage change from baseline was analyzed. Results A ow diagram of screened and randomized subjects is shown in gure 1. Most subjects (152 (96%)) completed the study. ree subjects were excluded

from the intent-to-treat population, one each in the placebo and 10 mg CCX140-B groups, because their medications were accidentally switched for the rst 2 weeks of the trial, while a third subject, in the pioglitazone group, was excluded because the subject did not receive any study medication. Eligible subjects were recruited from January 2010 until September 2010. Baseline demographics and characteristics are presented in table 1. e treatment groups were comparable with respect to demographic and baseline characteristics, except that the placebo group had a higher mean

baseline FPG (182.9 mg/dL) compared to the other treatment groups (166.0 mg/dL in the CCX140-B 5 mg group, 163.1 mg/dL in the CCX140-B 10 mg group, and 169.8 mg/dL in the pioglitazone group). Due to the inclusion criterion regarding BMI, the majority of subjects were obese with an average BMI of 32.1 ( 4.4) kg/m egarding the primary study objective, evaluation of the safety and tolerability of CCX140-B in subjects with type 2 diabetes, no serious adverse events (SAEs) were observed in subjects receiving CCX140-B. One subject, in the placebo group, experienced an SAE of syncope of

unknown origin for which the subject was hospitalized. Two subjects withdrew from the study due to a treatment-emergent adverse event (AE). One subject, in the CCX140-B 5 mg group, experienced an AE of dyspepsia, which led to discontinuation of study medication. Another subject, in the CCX140-B 10 mg group, experienced an AE of gouty arthritis, which led to discontinuation of study medication. is subject had a medical history of gout. In table 2, AEs reported by at least 3% of subjects in any treatment group during the 28-day treatment period are shown. Changes in safety laboratory

parameters, vital signs, and ECGs were not clinically meaningful (data not shown). Aer review of safety data at two time points during the study, the DMC recommended on both occasions to continue the study unchanged. Regarding the ecacy endpoints, the fasting plasma glucose levels over the course of the study are shown in gure 2A. e FPG proles indicate a CCX140-B dose-dependent decrease from baseline through day 29, with larger decreases observed during the 4-week treatment $VVHVVHG IR HO LW\Q 5DQGRPL]HG Q ([FOXGHG Q

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&&;%LQ7\SH'LDEHWHV$3LORW'RXEOH%OLQG5DQGRPL]HG&OLQLFDO7ULDO-'LDEHWHV0HWDEGRL period with 10 mg t han with 5 mg CCX140-B once daily. e least- squares mean change from baseline to day 29 (with the last observation carried forward) for FPG was -10.7, -4.3, -16.1 and -21.4 mg/dL in the placebo, CCX140-B 5 mg, CCX140-B 10 mg groups, and

pioglitazone groups, respectively (Table 3). e 10 mg CCX140-B and pioglitazone group least-squares mean decreases in FPG were comparable (-16.1 and -21.4 mg/dL, respectively; Table 3). e FPG decrease from baseline to day 29 in the two MCP-1 strata in the 10 mg CCX140-B group was similar, 16 mg/dL in the non-G polymorphism stratum and 17 mg/dL in the G stratum. CRP level changes in the 10 mg CCX140-B group over the 4-week treatment period were also similar in the two polymorphism strata: mean CRP changed from 2.9 to 3.2 mg/L (median from 2.0 to 1.6 mg/L) in the non-G stratum;

mean CRP changed from 3.5 to 3.0 mg/L (median from 2.2 to 1.8 mg/L) in the G stratum. e least-squares mean change from baseline in HbA 1c was -0.09%, -0.09%, -0.23%, and -0.13% in the placebo, CCX140-B 5 mg, CCX140-B 10 mg, and pioglitazone group, respectively (Figure 2B; Table 3). e 10 mg CCX140-B group decrease was signicantly dierent compared to the placebo group; p=0.045, Wilcoxon Rank Sum test. e fructosamine levels trended to be lower in the active dose groups compared to placebo (Table 3). Treatment with CCX140-B for 28 days in this study was not

associated with signicant changes from baseline to study day 29 in fasting plasma insulin, fasting HOMA-IR, glucose or insulin OGTT AUC, serum adiponectin, or hsCRP (Tables 3 and 4). e pioglitazone group showed the anticipated decrease in glucose OGTT AUC and hsCRP, and increase in serum adiponectin (Tables 3 and 4). CCX140-B treatment did not negatively aect the serum lipid proles (TC, HDL and LDL cholesterol, TG, or NEFAs) over the 4-week treatment period. Pioglitazone treatment increased HDL cholesterol, as anticipated (Table 4). CCX140-B treatment did not

aect plasma MCP-1 levels. Circulating monocyte counts were not changed by CCX140-B treatment (Table 4). ere was no signicant eect of CCX140-B treatment on body weight, and no evidence of hemodilution (based on hematocrit data) with CCX140-B treatment over the course of the clinical trial (Table 4). e mean ( SD) day 22 trough plasma concentration of CCX140 was 1370  548 ng/mL for the 5 mg CCX140-B dose group and 2450 1050 ng/mL for the 10 mg dose group, indicating that plasma exposure was dose-proportional. e mean apparent

half-life was 74.2  13.3 hours for the 5 mg dose group and 76.4  12.4 hours for the 10 mg dose group. Discussion is randomized, double-blind, placebo- and active-controlled, pilot Phase 2 clinical trial in 159 subjects with type 2 diabetes on a stable dose of metformin met its primary objective by demonstrating the safety and tolerability of CCX140-B over 28 days of dosing in these subjects. Pioglitazone was selected as an active comparator because at the time of study launch it was considered an eective and safe treatment for patients with type 2 diabetes with

a reproducible eect on glycemic parameters [8,9]. e subject study completion rate was 96%, supporting the good tolerability prole. No serious adverse events (SAEs) occurred in subjects receiving CCX140-B and only 2 subjects receiving CCX140-B discontinued early from the trial due to adverse events. Review of the adverse event prole in subjects receiving CCX140-B indicated no safety concerns. Review of serum chemistry, hematology, and urinalysis parameters indicated no safety concerns regarding hepatic, renal, metabolic, hematologic or immunologic systems. Of

particular note, there was no evidence of a detrimental eect of CCX140-B on circulating monocyte counts. A CCR2 antibody tested previously in a rheumatoid arthritis trial showed a 39% decrease in monocyte counts [10], indicating that not all CCR2 antagonists behave similarly in this regard. e reason for this dierence is unclear but may be related to a direct depleting eect of the CCR2 antibody on circulating monocytes or blockade of monocyte precursor release from bone marrow into the blood stream by the CCR2 antibody but not by the small molecule CCX140-B.

ere was no evidence of hemodilution with CCX140-B treatment based on hematocrit changes, or peripheral leg edema over the course of the trial. Electrocardiogram data and vital signs measurements over the course of the trial did not indicate any cardiovascular safety concerns with CCX140-B. e FPG proles over the course of the trial indicated a CCX140-B dose-dependent decrease from baseline over 4 weeks, with the 10 mg CCX140-B dose showing larger decreases than the 5 mg CCX140-B S 16 16

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+DQHIHOG 6FKHOO *RXQL%HUWKROG 0HOLFKDU 9HVHOD HWDO 2UDOO\$GPLQLVWHUHG&KHPRNLQH5HFHSWRU&&5$QWDJRQLVW

&&;%LQ7\SH'LDEHWHV$3LORW'RXEOH%OLQG5DQGRPL]HG&OLQLFDO7ULDO-'LDEHWHV0HWDEGRL group. e magnitude of the decrease from baseline in FPG was relatively similar in the CCX140-B 10 mg once daily group compared to the active drug pioglitazone (least-squares mean change from baseline to day 29 of -16.1 compared to -21.4 mg/dL, respectively). e

decrease from baseline in FPG of 21.4 mg/dL with pioglitazone 30 mg was in line with the decrease of approximately 25 mg/dL over 4 weeks of treatment reported previously for this drug [8,9]. Results from the 4-week change from baseline in HbA 1c are consistent with the glucose-lowering eect seen with the CCX140-B 10 mg group. Four weeks are obviously not long enough to fully elucidate the anti-glycemic eect of most drugs for diabetes treatment. Nevertheless, the least squares mean decrease in HbA 1c of 0.23% over 4 weeks observed with 10 mg CCX140-B is consistent with the 0.2

to 0.4% decrease observed with other eective anti-diabetic treatments such as thiazolidinediones, glucagon-like peptide-1 analogs, incretin mimetics, dipeptidyl peptidase-4 inhibitors, and an IL-1 receptor antagonist [8,11-16]. Now that long-term toxicology data are available with CCX140-B, longer term clinical trials have been initiated to more fully elucidate the eect of CCX140-B on HbA 1c Of note is that the results with CCX140-B were achieved as add-on treatment to metformin which is recommended in all guidelines as rst line drug for type 2 diabetes. Furthermore, we

selected patients with BMI25kg/m resulting in an average BMI of 32 kg/m , since inamed adipose tissue is thought to be the major target organ of CCR2 receptor antagonists [3-5]. us, t he signicant eect of CCX140-B may be considered as proof of principle of the potential benecial eects of add-on treatment with such a new class of drugs. ere were no detrimental eects of CCX140-B treatment on plasma MCP-1 levels. is is in contrast to what has been observed with other CCR2 antagonists tested in animals and humans

[10,17- 19]. It is unclear why these dierences have been observed, but it may be due to relative specicity of the various compounds for CCR2, pharmacokinetic prole dierences of the drugs, or the nature of the interaction between various antagonists and CCR2, for example with macro-molecules such as antibodies compared to small molecules such as CCX140-B. Treatment with CCX140-B for 28 days in this study was not associated with signicant changes from baseline in other glycemic parameters. is suggests that improving insulin sensitivity may not be

the major driver of anti-glycemic eects of CCX140-B 10 mg in humans based on the FPG and HbA 1c decreases observed over 4 weeks of treatment. Other possible modes of action include a decrease in hepatic gluconeogenesis and possible improvement in beta cell function through its anti-inammatory eect, as has been observed with the anti-inammatory drug IL-1 ra [16]. It is also possible that the 4-week treatment period was too short to fully evaluate the eect of CCX140-B treatment on measurements of insulin sensitivity. CCX140-B treatment did not negatively

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Page 7
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2UDOO\$GPLQLVWHUHG&KHPRNLQH5HFHSWRU&&5$QWDJRQLVW &&;%LQ7\SH'LDEHWHV$3LORW'RXEOH%OLQG5DQGRPL]HG&OLQLFDO7ULDO-'LDEHWHV0HWDEGRL proles over the 4-week treatment period and there was no signicant eect of CCX140-B treatment on

body weight or hematocrit over the course of the trial. It was of interest to assess whether a previously identied polymorphism in the MCP-1 promoter region (bp: -2518, G vs. non-G) would inuence the glycemic or CRP changes in response to a CCR2 antagonist, since a previous report indicated that there might be a dierence in these populations [20]. e FPG data in the two strata (G vs. non-G) did not provide evidence that the anti-glycemic eect of CCX140-B diers between the two strata. CRP changes in the two strata were also not dierent.

However, it should be noted that the sample size in each stratum in our study was relatively small, and the CRP levels at baseline in our study were lower than the levels reported in the study from Gilbert et al. [20]. CCX140 in plasma showed a long terminal half-life based on plasma concentration measurements. e trough plasma concentrations were also consistent with the long plasma half-life of CCX140, which makes it suitable for low dose once daily dosing in humans. Limitations of the clinical trial include the relatively small size and short duration of the study. Larger and longer

term clinical trials are in progress. is clinical trial met its primary objective by demonstrating that treatment with CCX140-B was safe and well tolerated. No safety issues were identied in this study. FPG and HbA 1c results with CCX140-B treatment, although not denitive, are encouraging. If conrmed by further clinical trials, blocking CCR2 might provide a novel mechanism to treat diabetes and its complications. Longer-term clinical trials in patients with diabetic nephropathy are currently underway to further evaluate the safety and ecacy of CCX140-B

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&LWDWLRQ +DQHIHOG 6FKHOO *RXQL%HUWKROG 0HOLFKDU 9HVHOD HWDO

2UDOO\$GPLQLVWHUHG&KHPRNLQH5HFHSWRU&&5$QWDJRQLVW &&;%LQ7\SH'LDEHWHV$3LORW'RXEOH%OLQG5DQGRPL]HG&OLQLFDO7ULDO-'LDEHWHV0HWDEGRL Appendix In addition to the primary authors, the following investigators participated in the CCX140-B Diabetes Study and

recruited subjects: Australia – Robyn Huttenmeister, AusTrials Party Ltd., Auchenower; Je Karrasch and Bridget Healy, AusTrials Party Ltd., Kippa Ring; Czech Republic – Dagmar Bartškov, Diabetologick ambulance Milan Kvapil s.r.o., Prague; Ivana Burešov, Intern a diabetologick ambulance, Beroun; Petr Chmura, Intern a diabetologick ambulance, Ostrava; Daniel Kubina, Ordinace praktickeho lekare, Hlucin; Michal Labuť, steck poliklinika s.r.o., st nad Labem; Vladimr Lelek,

Poliklinika Slan, Slan; Eva Parmov, Diabetologick ambulance - Uhersk Brod, Uhersk Brod; Pavlna Paulyskov, Intern a diabetologick ambulance, Přelouč; Vladimr Polk, Diabetologick ambulance, Nov Jičn; Tomš Spousta, Genom, s.r.o., Ostrava; Marcela Szab, Intern a diabetologick ambulance – Neratovice, Neratovice; Vclav Zamrazil, I.D.E. s.r.o., Prague; Germany – Hasan Alawi, Private Practice, Saarlouis; Christoph Hasslacher,

Diabetesinstitut Heidelberg, Heidelberg; Ursula Plckinger, Charite Berlin Campus Virchow-Klinikum, Berlin; Petra Stuebler, Private Practice, Mannheim; Hungary – Akos Kalina, HM Allami Egeszsegugyi Kozpont Szakrendelo, Budapest; Laszlo Koranyi, DRC K., Balatonfuered; Karoly Nagy, Synexus Magyarorszag K., Budapest; Zsolt Ples, Erzsebet Korhaz Satoraljaujhely- Dental-Med Co, Satoraljaujhely; Imre Szentpeteri, Rakoczi Ferenc Korhaz-CRU Hungary, Szikszo; Peter Voros, Szent Istvan Hospital, Budapest; New Zealand – Dean Quinn, P3 Research Ltd., Wellington; Russell Scott,

Christchurch Hospital, Christchurch.