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117: Open Label, Placebo-Controlled, Randomized, Single Dose Escalation and Repeat Dose Study of Intravenous CTA018 in Healthy Volunteers
NKF 2008 Spring Clinical Meetings Abstracts
117 OPEN LABEL, PLACEBO-CONTROLLED, RANDOMIZED, SINGLE DOSE ESCALATION AND REPEAT DOSE STUDY OF INTRAVENOUS CTA018 IN HEALTHY VOLUNTEERS. Jukka Karjalainen1, Jeffery Warren 1, Joel Z Melnick1 and Jonathan Willmer 2; 1Cytochroma Inc. Markham, Ontario, Canada; 2CANTEST Clinical Research, Vancouver, British Columbia, Canada. Vitamin D hormone analogs are commonly used to treat secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, but are often associated with hypercalcemia and hyperphosphatemia. CTA018 is a novel vitamin D analog with dual mechanism of action: 1) it binds to vitamin D receptors, which activate vitamin D signaling pathways and 2) it inhibits 24-hydroxylase (CYP24), the enzyme that inactivates vitamin D. This study evaluated the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of intravenous CTA018 in healthy volunteers. During (Stage I) the single-dose phase, CTA018 or placebo was administered every 4 days to 10 (7 active: 3 placebo) healthy volunteers at doses of 10µg, 30µg, 60µg, 90µg, 120µg, 150µg and 180µg. Two doses, 90µg and 180µg, were selected for repeat administrations in Stage II; in both groups, 10 (8 active: 2 placebo) volunteers received intravenous CTA018 or placebo 5 times over 10 days. In Stage I, none of the doses administered affected Ca, P or PTH. In Stage II, no significant differences in tmax, T½, Vd and clearance were observed between the two doses. There was no accumulation of CTA018, most likely due to a short elimination half-life of ~2 hours. In the 180µg dose group, mean and median plasma iPTH levels were reduced over 20%, which was clinically significant. No increase in serum or urine Ca or P was observed. In the 90µg and 180µg groups, the median 25(OH)D3 levels increased by 27% and 63% respectively from baseline, compared to 6% increase in the placebo group. There were no deaths or serious adverse events and primary safety parameters (chemistry, hematology and urinalysis) were comparable between placebo and CTA018 treated groups. In healthy volunteers, intravenous CTA018 was observed to be safe up to a dose of 180µg, which reduced iPTH without affecting Ca or P. The observed increase in 25(OH)D3 levels may suggest that CTA018 reduces CYP24-mediated catabolism of 25(OH)D3.
118 HOMOCYSTEINE LOWERING EFFECT OF ADSORPTIVE DIALYSIS MEMBRANES: A MULTICENTER, RANDOMIZED, OPEN STUDY Amir Kazory*, Marc Kribs, Véronique Fournier, Gérard Motte, Claude Guy, Nadège Devillard, Maria Yann araki, Gilbert Zanetta, Jean-Marc Chalopin, Véronique Fayol, Didier Ducloux* * Department of Nephrology, Dialysis, and Renal Transplantation, University of Franche-Comté, Besançon, France Background: hyperhomocysteinemia is prevalent in patients with renal failure. Previous studies have suggested that removal of uremic toxins is the main mechanism for homocysteine-lowering effect of dialysis. It is not known whether adsorptive membranes can offer a similar or greater impact over commonly used polysulfone filters. Methods: This prospective randomized study was designed to evaluate the potential role of adsorptive membranes in providing a sustained reduction in total plasma homocysteine (tHcy) levels. After a four-week wash-out period using a cellulosic membrane, patients were randomized to either a polysulfone or a polyester-polymer-alloy (PEPA) membrane for eight weeks. tHcy levels as well as serum folate concentrations and other relevant parameters were measured. Results: Fifty two patients were included in this study. tHcy levels were highly related to folate concentrations (r=-0.50; p=0.0007). The mean intra-dialytic decrease in tHcy was similar with all membranes. At the end of the study, tHcy did not significantly differ between the two groups (20.2 +/- 7.2 µmol/l vs 22.9 +/- 7.2, in the PEPA and polysulfone groups, respectively; p=0.18). Nevertheless, while mean tHcy concentration remained stable in the polysulfone group (22.6 +/6.3 vs 22.9 +/- 7.2 µmol/l; p=0.48), a significant decrease was observed in the PEPA group (22.7 +/- 7.5 vs 20.2 +/- 7.2 µmol/l; p<0.0001). Also, the variation in tHcy was +1.4% and -10.9% in the polysulfone and in the PEPA groups respectively (p=0.02). Conclusion: Despite equivalent sieving properties and tHcy clearance, the membrane with high adsorptive capacity (PEPA) can reduce tHcy levels more efficiently at long-term compared with the commonly used polysulfone membranes.
A57
119 25-HYDROXYVITAMIN D AND INFLAMMATION AND ITS ASSOCIATION WITH HEMOGLOBIN LEVELS IN CHRONIC KIDNEY DISEASE Jessica Kendrick, Gerard Smits, Michel Chonchol. University of Colorado Health Sciences Center, Denver, CO, USA. Anemia associated with chronic kidney disease (CKD) has substantial public health importance. However, the association of hemoglobin concentrations with 25-hydroxyvitamin D (25(OH)D) levels and inflammation in the setting of decreased kidney function is not well established. A population-based sample of 16301 participants 18 years and older in the Third National Health and Nutrition Examination Survey, conducted from 1988 to 1994, was analyzed. Glomerular filtration rate (eGFR) in mL/min/1.73 m2 was estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Multivariate linear regression analyses were performed to identify factors independently associated with hemoglobin concentrations. There were significant, graded, increases in C-reactive protein (CRP) and decreases in 25(OH)D levels and hemoglobin concentrations across eGFR categories: ≥90; 89-60; 59-30; 29-15 mL/min/1.73m2 (p<0.0001 for linear trend). In multivariate analysis, lower 25(OH)D (p=0.0014) and eGFR (p<0.0001) levels and higher CRP (p< 0.0001) levels were associated with a decrease in hemoglobin concentrations after adjustment for age, gender, race, weight, systolic and diastolic blood pressure, baseline eGFR, microalbuminuria and lipid and glucose levels. The same findings were obtained in multivariate logistic regression models in which hemoglobin was entered as a categorical variable (≤12g/dL) instead of a continuous measure. Low 25(OH)D and elevated CRP levels are independently associated with lower hemoglobin concentrations, explaining much of the high prevalence of anemia in persons with kidney disease.
120 25-HYDROXYVITAMIN D, CARDIOVASCULAR DISEASE AND KIDNEY FUNCTION IN THE THIRD NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY Jessica Kendrick, Gerard Smits, Michel Chonchol. University of Colorado Health Sciences Center, Denver, CO, USA Previous research has reported reduced serum 25hydroxyvitamin D (25(OH)D) levels in patients with chronic kidney disease (CKD). However, the relationship between vitamin D status and cardiovascular disease (CVD) in patients with CKD has not been examined in the general population. We analyzed data from 16864 subjects over the age of 18 who participated in the Third National Health and Nutrition Examination Survey (NHANES III). CKD was defined according to the Modification of Diet in Renal Disease equation as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. CVD was defined as a composite of selfreported angina, myocardial infarction and stroke. Logistic regression analysis was applied to examine the association between 25(OH)D levels with self-reported CVD. Among 16864, there were 1871 subjects with self-reported CVD and 1016 participants with CKD. In multivariate analysis there was a significant relationship between decreasing quintiles of 25(OH)D level and prevalent CVD in the whole population (adjusted odds ratios and 95% confidence intervals) 1.0 (top quintile reference group), 1.16 (0.97-1.38), 1.18 (0.98-1.41),1.34 (1.11-1.62), and 1.33 (1.09-1.63). No significant association was found between 25(OH)D levels and prevalent CVD in participants with CKD (p: 0.63). Serum 25(OH)D levels are associated with prevalent CVD in US adults. Further studies are necessary to elucidate the role of 25(OH)D deficiency in the pathway by which CKD contributes to CVD.
117 OPEN LABEL, PLACEBO-CONTROLLED, RANDOMIZED, SINGLE DOSE ESCALATION AND REPEAT DOSE STUDY OF INTRAVENOUS CTA018 IN HEALTHY VOLUNTEERS. Jukka Karjalainen1, Jeffery Warren 1, Joel Z Melnick1 and Jonathan Willmer 2; 1Cytochroma Inc. Markham, Ontario, Canada; 2CANTEST Clinical Research, Vancouver, British Columbia, Canada. Vitamin D hormone analogs are commonly used to treat secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, but are often associated with hypercalcemia and hyperphosphatemia. CTA018 is a novel vitamin D analog with dual mechanism of action: 1) it binds to vitamin D receptors, which activate vitamin D signaling pathways and 2) it inhibits 24-hydroxylase (CYP24), the enzyme that inactivates vitamin D. This study evaluated the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of intravenous CTA018 in healthy volunteers. During (Stage I) the single-dose phase, CTA018 or placebo was administered every 4 days to 10 (7 active: 3 placebo) healthy volunteers at doses of 10µg, 30µg, 60µg, 90µg, 120µg, 150µg and 180µg. Two doses, 90µg and 180µg, were selected for repeat administrations in Stage II; in both groups, 10 (8 active: 2 placebo) volunteers received intravenous CTA018 or placebo 5 times over 10 days. In Stage I, none of the doses administered affected Ca, P or PTH. In Stage II, no significant differences in tmax, T½, Vd and clearance were observed between the two doses. There was no accumulation of CTA018, most likely due to a short elimination half-life of ~2 hours. In the 180µg dose group, mean and median plasma iPTH levels were reduced over 20%, which was clinically significant. No increase in serum or urine Ca or P was observed. In the 90µg and 180µg groups, the median 25(OH)D3 levels increased by 27% and 63% respectively from baseline, compared to 6% increase in the placebo group. There were no deaths or serious adverse events and primary safety parameters (chemistry, hematology and urinalysis) were comparable between placebo and CTA018 treated groups. In healthy volunteers, intravenous CTA018 was observed to be safe up to a dose of 180µg, which reduced iPTH without affecting Ca or P. The observed increase in 25(OH)D3 levels may suggest that CTA018 reduces CYP24-mediated catabolism of 25(OH)D3.
118 HOMOCYSTEINE LOWERING EFFECT OF ADSORPTIVE DIALYSIS MEMBRANES: A MULTICENTER, RANDOMIZED, OPEN STUDY Amir Kazory*, Marc Kribs, Véronique Fournier, Gérard Motte, Claude Guy, Nadège Devillard, Maria Yann araki, Gilbert Zanetta, Jean-Marc Chalopin, Véronique Fayol, Didier Ducloux* * Department of Nephrology, Dialysis, and Renal Transplantation, University of Franche-Comté, Besançon, France Background: hyperhomocysteinemia is prevalent in patients with renal failure. Previous studies have suggested that removal of uremic toxins is the main mechanism for homocysteine-lowering effect of dialysis. It is not known whether adsorptive membranes can offer a similar or greater impact over commonly used polysulfone filters. Methods: This prospective randomized study was designed to evaluate the potential role of adsorptive membranes in providing a sustained reduction in total plasma homocysteine (tHcy) levels. After a four-week wash-out period using a cellulosic membrane, patients were randomized to either a polysulfone or a polyester-polymer-alloy (PEPA) membrane for eight weeks. tHcy levels as well as serum folate concentrations and other relevant parameters were measured. Results: Fifty two patients were included in this study. tHcy levels were highly related to folate concentrations (r=-0.50; p=0.0007). The mean intra-dialytic decrease in tHcy was similar with all membranes. At the end of the study, tHcy did not significantly differ between the two groups (20.2 +/- 7.2 µmol/l vs 22.9 +/- 7.2, in the PEPA and polysulfone groups, respectively; p=0.18). Nevertheless, while mean tHcy concentration remained stable in the polysulfone group (22.6 +/6.3 vs 22.9 +/- 7.2 µmol/l; p=0.48), a significant decrease was observed in the PEPA group (22.7 +/- 7.5 vs 20.2 +/- 7.2 µmol/l; p<0.0001). Also, the variation in tHcy was +1.4% and -10.9% in the polysulfone and in the PEPA groups respectively (p=0.02). Conclusion: Despite equivalent sieving properties and tHcy clearance, the membrane with high adsorptive capacity (PEPA) can reduce tHcy levels more efficiently at long-term compared with the commonly used polysulfone membranes.
A57
119 25-HYDROXYVITAMIN D AND INFLAMMATION AND ITS ASSOCIATION WITH HEMOGLOBIN LEVELS IN CHRONIC KIDNEY DISEASE Jessica Kendrick, Gerard Smits, Michel Chonchol. University of Colorado Health Sciences Center, Denver, CO, USA. Anemia associated with chronic kidney disease (CKD) has substantial public health importance. However, the association of hemoglobin concentrations with 25-hydroxyvitamin D (25(OH)D) levels and inflammation in the setting of decreased kidney function is not well established. A population-based sample of 16301 participants 18 years and older in the Third National Health and Nutrition Examination Survey, conducted from 1988 to 1994, was analyzed. Glomerular filtration rate (eGFR) in mL/min/1.73 m2 was estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Multivariate linear regression analyses were performed to identify factors independently associated with hemoglobin concentrations. There were significant, graded, increases in C-reactive protein (CRP) and decreases in 25(OH)D levels and hemoglobin concentrations across eGFR categories: ≥90; 89-60; 59-30; 29-15 mL/min/1.73m2 (p<0.0001 for linear trend). In multivariate analysis, lower 25(OH)D (p=0.0014) and eGFR (p<0.0001) levels and higher CRP (p< 0.0001) levels were associated with a decrease in hemoglobin concentrations after adjustment for age, gender, race, weight, systolic and diastolic blood pressure, baseline eGFR, microalbuminuria and lipid and glucose levels. The same findings were obtained in multivariate logistic regression models in which hemoglobin was entered as a categorical variable (≤12g/dL) instead of a continuous measure. Low 25(OH)D and elevated CRP levels are independently associated with lower hemoglobin concentrations, explaining much of the high prevalence of anemia in persons with kidney disease.
120 25-HYDROXYVITAMIN D, CARDIOVASCULAR DISEASE AND KIDNEY FUNCTION IN THE THIRD NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY Jessica Kendrick, Gerard Smits, Michel Chonchol. University of Colorado Health Sciences Center, Denver, CO, USA Previous research has reported reduced serum 25hydroxyvitamin D (25(OH)D) levels in patients with chronic kidney disease (CKD). However, the relationship between vitamin D status and cardiovascular disease (CVD) in patients with CKD has not been examined in the general population. We analyzed data from 16864 subjects over the age of 18 who participated in the Third National Health and Nutrition Examination Survey (NHANES III). CKD was defined according to the Modification of Diet in Renal Disease equation as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. CVD was defined as a composite of selfreported angina, myocardial infarction and stroke. Logistic regression analysis was applied to examine the association between 25(OH)D levels with self-reported CVD. Among 16864, there were 1871 subjects with self-reported CVD and 1016 participants with CKD. In multivariate analysis there was a significant relationship between decreasing quintiles of 25(OH)D level and prevalent CVD in the whole population (adjusted odds ratios and 95% confidence intervals) 1.0 (top quintile reference group), 1.16 (0.97-1.38), 1.18 (0.98-1.41),1.34 (1.11-1.62), and 1.33 (1.09-1.63). No significant association was found between 25(OH)D levels and prevalent CVD in participants with CKD (p: 0.63). Serum 25(OH)D levels are associated with prevalent CVD in US adults. Further studies are necessary to elucidate the role of 25(OH)D deficiency in the pathway by which CKD contributes to CVD.