New Medicines Profile December 2013 Issue. 13/04 Concise evaluated information to support the managed entry of new medicines in the NHS Summary (BindRen ) is an oral, non-absorbed, non-calcium, nonmetallic binder licensed to treat hyperphosphataemia in adults receiving dialysis for stage 5 chronic kidney disease. Studies lasting up to 12 months show colestilan, in doses of 12 to 15g daily, lowers mean levels by a clinically significant amount ( 0.3mmol/L) compared with placebo. About 50% of patients taking colestilan achieve levels 1.78mmol/L. has no effect on calcium levels. It significantly reduces calcium x ion product and cholesterol levels compared with placebo. In an open-label study powered to assess non-inferiority, 43% of patients on colestilan for 12 weeks achieved a level of 1.78mmol/L compared with 68% on sevelamer; non-inferiority could not be concluded. However, in patients who continued for one year, responder rates were similar. There are no studies assessing the effects of colestilan on patientoriented outcomes. Pooled safety data from 1,410 adults given colestilan show 45% experienced gastrointestinal (GI) adverse events which led to 10% stopping. More patients on colestilan than on sevelamer reported GI adverse events, but the data may have been biased against colestilan. NICE recommends calcium acetate as first-line binder in adults; if not tolerated, calcium carbonate may be used. ncalcium-based binders can be used instead or added if levels remain high despite using the maximum recommended or tolerated dose. is an alternative to binders such as sevelamer hydrochloride and lanthanum in these patients, although its efficacy in combination with calcium-based binders is unknown. granules are an option for people unable to swallow tablets, but there are no data to show that compliance is improved. Brand Name, (Manufacturer): BindRen, (Mitsubishi Pharma Europe). BNF Therapeutic Class: 9.5.2.2 Phosphate-binding agents. Licensed Indications: Treatment of hyperphosphataemia in adults with stage 5 chronic kidney disease on haemodialysis or peritoneal dialysis. Dosage and Administration: 2-3g three times daily, with or immediately after meals. Increase the dose by 3g daily at two to three weekly intervals to a maximum of 15g daily, until acceptable levels are achieved. Available as 1g tablets, and sachets containing 2g or 3g odourless and flavourless oral granules. Marketed: vember 2013. Cost Comparisons: For 28 days (BNF/MIMS Dec 2013). N.B. Doses shown for general comparison and do not imply therapeutic equivalence. Introduction is an oral binder licensed to treat hyperphosphataemia in adults receiving dialysis for stage 5 chronic kidney disease (CKD-5). 1 It is an anionexchange resin that lowers serum levels by binding from food (releasing chloride ions), and also binds bile acids reducing absorption of cholesterol and glucose. 1 It is not absorbed and does not contain calcium or aluminium. has been available in Japan since 1999 to treat hypercholesterolaemia at doses up to 4g daily. 2 About 26,000 people with CKD in the UK receive dialysis; 3 nearly all have hyperphosphataemia. 4 High levels are usually asymptomatic but can cause pruritus, bloodshot eyes and joint pain, and are accompanied by hypocalcaemia, low vitamin D levels and hyperparathyroidism. 5 Untreated, these biochemical changes may lead to abnormalities of bone turnover (causing fracture and disability), and soft tissue and vascular calcification (leading to muscle pain and cardiovascular (CV) disease) a condition known as CKD mineral and bone disorder (CKD-MBD). 5,6 Half of patients with stage 4 or 5 CKD have CV disease, 7 and CV mortality rates are 10 to 20 times higher in patients on dialysis than the general population. 6 Several large observational studies in patients on dialysis have shown all-cause mortality increases with rising levels. 4 The DOPPS study showed that the greatest risk of death is associated with levels of 2.26mmol/L or higher, and risk is significantly lower with each 0.3mmol/L reduction. 2,8 However, no -lowering interventions have been shown in controlled trials to reduce mortality in patients on dialysis. 4,9 For adults with CKD-5 receiving dialysis, guidelines recommend levels should be kept between 1.1 and 1.7mmol/L; currently this is achieved in about two thirds of patients. 3 Hyperphosphataemia is managed by limiting intake of -rich foods, using binders such as calcium-based binders, sevelamer, lanthanum, magnesium-based binders and aluminium hydroxide, and partial removal by dialysis. 3 Evidence Three pivotal phase III studies (A05, E07 and E08) and several supportive studies, including two long-term studies (A06 and E10), have assessed efficacy and safety of colestilan in managing hyperphosphataemia in patients with CKD-5 receiving haemodialysis (94%) or peritoneal dialysis. 2,10-13 All studied the effect of colestilan tablets on levels and surrogate measures of CKD-BMD such as calcium x ion product (CaxP); none assessed hyperphosphataemia symptoms, progression of vascular calcification or patient-oriented outcomes such as fracture. Analysis of primary outcomes in the pivotal studies was on the intention-to-treat population.
A05 and E07 were similar 12-week openlabel studies each followed by a fourweek double-blind withdrawal period during which colestilan was compared with placebo. After undergoing washout of previous binders, patients were given colestilan 6g daily (in E07 they were to colestilan or sevelamer) and their dose titrated to achieve levels between 1.13 and 1.78mmol/L. After 12 weeks, patients in the colestilan groups were to continue colestilan or switch to placebo. The primary objective was to show colestilan was superior to placebo in controlling levels; secondary objectives included control of calcium, parathyroid hormone (PTH), CaxP and cholesterol, and E07 was also powered to compare colestilan with sevelamer. 2,11 Treatment with colestilan for 12 weeks (mean dose 11.5g in A05 and 13.1g in E07) resulted in clinically significant reductions in mean levels ( 0.3mmol/L). In both trials, levels were 1.78mmol/L or lower in about 45% of patients at 12 weeks. Patients with baseline levels 2.44mmol/L had larger decreases in levels than those with lower baseline levels. At 16 weeks, the proportion of responders in the colestilan groups stayed about the same but fell to 20% in those switched to placebo. The difference between colestilan and placebo in mean level was 0.33mmol/L in A05 and 0.43mmol/L in E07. Compared with placebo, colestilan had no effect on calcium levels, and significantly reduced CaxP, and PTH and cholesterol levels. 2,11 In E07, non-inferiority of colestilan to sevelamer could not be concluded mean level in patients on sevelamer for 12 weeks was 0.3mmol/L lower than with colestilan, and 68% achieved a level of 1.78mmol/L or lower compared with 43% on colestilan. 2,11 One third of patients had previously taken sevelamer, and tolerance to its adverse effects and the open-label nature of the study could have favoured sevelamer. By contrast, in patients from E07 who continued in the 52-week extension E10 study, about twothirds on colestilan and sevelamer achieved levels of 1.78mmol/L or lower. 2 However, patient numbers were small (75 and 124, respectively) and a large number subsequently dropped out (42% and 26%, respectively). 11 Also, these responder rates are higher than in long-term studies overall (see later). E08 was a fixed-dose study in which patients were to different doses of colestilan (3g, 6g, 9g, 12g or 15g) or placebo for 12 weeks. 10 Primary outcome was change in and low-density lipoprotein (LDL)-cholesterol levels. reduced levels in a dose-dependent manner, but only 12g and 15g doses produced clinically significant reductions compared with placebo. LDL-cholesterol was significantly reduced with all doses. There were no differences between colestilan and placebo in calcium and PTH levels. 2,10 About one-third of patients taking colestilan withdrew during the open-label periods of A05 and E07, mostly in the first five weeks due to adverse events (AE) (9 and 17%, respectively) or lack of efficacy (5%, both). The EU Committee for Medicinal Products for Human Use asked the manufacturer to conduct an analysis counting all withdrawals as nonresponders. This confirmed that colestilan significantly reduces levels (responder rate 41 to 52% across all three pivotal trials). 2 Long-term open-label studies (A06 and E10) show colestilan lowers levels for up to one year (combined data: mean level 1.89mmol/L; mean reduction from baseline 0.39mmol/L), with no decrease in the proportion of responders (44%). 1,2 Most patients needed doses of 12g or 15g daily. 1 Safety Pooled data from trials involving 1,410 adults given colestilan for up to a year show dose-related gastrointestinal (GI) AEs (nausea, vomiting, abdominal pain, dyspepsia, diarrhoea and constipation) were most common. They occurred in 45% of patients and led to 10% stopping colestilan. 2 In E07, 49% of patients reported GI AEs with colestilan and 36% with sevelamer (but a third were possibly tolerant of sevelamer). 2 safety data are available from small PII studies comparing colestilan with calcium acetate, 2 and limited long-term data have been published. 11,13 should not be used in patients with swallowing problems, seizure disorders, recent peritonitis, or severe GI disorders or liver impairment as patients with these conditions were excluded from trials. 1 Patients with constipation should be monitored. 1 may impair vitamin K absorption, increasing risk of bleeding; in trials, GI bleeding rates were similar with colestilan and sevelamer. Acidosis is possible but was not reported. 2 NHS Impact The ideal binder avidly binds dietary, is inexpensive, is minimally absorbed, and has few side effects and a low pill burden. 4 ne currently available, including colestilan, meet all these criteria. The National Institute for Health and Care Excellence (NICE) recommends calcium acetate as first-line binder in adults; if not tolerated, calcium carbonate may be used. 3 If levels remain high despite using the maximum possible dose, non-calcium-based binders can be used instead or added. Lanthanum or sevelamer hydrochloride can be considered if the patient is hypercalcaemic or has low PTH levels. NICE did not review data for colestilan. is effective at reducing levels in doses of 12 to 15g daily, but it may take several weeks to achieve recommended levels. It is an alternative to other non-calcium-based binders, but trials are needed comparing the effect of colestilan with other binders on patient-oriented outcomes, and assessing its efficacy in combination with calcium-based binders. 14 The main reason for failure with binders is poor compliance. 6 NICE noted the large size of calcium acetate tablets which may affect compliance; colestilan tablets are of a similar size (20mm by 11mm). 15 Compliance could also be affected by the high pill burden as, to be effective, most patients need between 12 and 15 tablets daily. Like sevelamer suspension and lanthanum powder, colestilan granules (taken with sufficient water to aid swallowing) are an option for patients unable to swallow tablets. However, there are no data available to show improved compliance with granules. s ability to lower LDLcholesterol levels may be useful in some patients, but raised levels are not typical of advanced CKD. 7 Appendix I: Tables of trials. Risk Management Issues: tablets and granules should be swallowed whole, with or immediately after meals, with sufficient water to aid swallowing. 1 may reduce absorption of medicines and fat-soluble vitamins take medicines that could be significantly affected 1 hour before or 3 hours after colestilan see SmPC. Interaction studies have only been done with doses 9g daily. 1 Further studies are planned. 2 Produced for the UK Medicines Information Service By Joanne McEntee rth West Medicines Information Centre, 70 Pembroke Place, Liverpool L69 3GF Tel: 0151 794 8117 email: nwmedinfo@nhs.net The information contained in this document will be superseded in due course. t to be used for commercial purposes. May be copied for use within the NHS.
erences 1. Summaries of Product Characteristics: BindRen, 1g film-coated tablets and 2g/3g granules. Mitsubishi Pharma Europe Ltd. 8 August 2013. 2. BindRen. European Public Assessment Report Scientific discussion. Available at www.emea.europa.eu/docs/en_gb/document_library /EPAR_- _Public_assessment_report/human/002377/WC5001 39167.pdf Accessed 15/10/13. 3. National Institute for Health and Clinical Excellence. Hyperphosphataemia in chronic kidney disease. Management of hyperphosphataemia in patients with stage 4 or 5 chronic kidney disease. March 2013. Available at http://guidance.nice.org.uk/cg157 Accessed 15/10/13. 4. Tonelli M, Pannu N and Manns B. Oral binders in patients with kidney failure. New Eng J Med 2010; 362: 1312-24. 5. Raymond CB, Wazny LD and Sood AR. Update on the new Kidney Disease; Improving Global Outcomes (KDIGO) guidelines for mineral and bone disorders (MBD) A focus on medications. CANNT J 2010; 20: 42-6. 6. Connor A. vel therapeutic agents and strategies for the management of chronic kidney disease mineral and bone disorder. Postgrad Med J 2009; 85: 274-9. 7. The National Collaborating Centre for Chronic Conditions. Chronic Kidney Disease. National clinical guideline for early identification and management in adults in primary and secondary care. Available at http://www.nice.org.uk/nicemedia/live/12069/42116 /42116.pdf Accessed 15/10/13. 8. Tentori F, Blayney MJ, Albert JM, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2008; 52: 519-30. 9. Frazao JM and Adragao T. n-calcium-containing binders: Comparing efficacy, safety, and other clinical effects. Nephron Clin Pract 2012; 120: c108-19. 10. Locatelli F, Dimkovic N and Spasovski G. Evaluation of colestilan in chronic kidney disease dialysis patients with hyperphosphataemia and dyslipidaemia: a randomized, placebo-controlled, multiple fixeddose trial. Nephrol Dial Transplant 2013; 28: 1874-88. 11. Locatelli F, Spasovski G, Dimkovic N, et al. The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study. Nephrol Dial Transplant 2013 (in press). 12. Hertel JE et al. (MCI-196), a new calcium-free binder, is safe and effective in stage 5 CKD dialysis patients: Phase 3, randomized, double-blind (DB), placebo (PBO)-controlled, multicenter study. ASN Renal Week 2010; Abstracts: Abs F- PO1862. 13. Senatore F et al. A, open-label, flexible dose, long-term safety study of colestilan in chronic kidney disease stage V subjects on dialysis with hyperphosphataemia. Nephrol Dial Transplant 2012; 27(suppl 2): Abs SAO057. 14. Navaneethan SD, Palmer SC, Vecchio M, Craig JC, Elder GJ, Strippoli GFM. Phosphate binders for preventing and treating bone disease in chronic kidney disease patients. Cochrane Database of Systematic Reviews 2011, Issue 2. Art..: CD006023. 15. Senatore F et al. (A13) Acceptability of a granule formulation of the new binder colestilan in healthy subjects. Poster presented at the 41 st EDTNA/ERCA international conference 2012. Key papers are highlighted in bold
Appendix I Table 1. Flexible-dose trials. Trial design Placebo $ LS mean difference [95% CI] A05 12) Double-blind, flexible-dose, (45), withdrawal PIII trial. The study consisted of: a 1-5 week washout period for current binders, a 12-week open-label flexibledose titration period with all patients given colestilan, and a 4-week doubleblind, placebo controlled withdrawal period. Patients with chronic kidney disease stage 5. Serum 1.94mmol/L and 15% rise at baseline after washout of binders, or 2.58mmol/L and 15% rise at any time during washout. Haemodialysis or peritoneal dialysis. Stable low diet. Phosphate level >2.97mmol/L during periods. additional information available, but reported as being similar to those in study E07. 2 Open-label, flexible-dose period (baseline to week 12): 245 patients enrolled. ITT population, n=241 (114 men), mean age 56 years (range 22 to 84). All patients started on colestilan 6g/day for two weeks and then titrated up or down by 3g/day weekly to maximum 15g/day, until serum between 1.13 and 1.78mmol/L. Double-blind period (week 12 to 16): 169 patients, 85 colestilan, 84 placebo. ITT population, n=168. Baseline data Mean (SD) levels: pre-washout 5.14mg/dL (1.0) (=1.67mmol/L). at baseline 7.55mg/dL (1.7) (=2.44mmol/L). Primary outcome. Change from week 12 to 16 (or LOCF) in mean [SD] serum levels of: Phosphate, mg/dl -0.04 [1.5] 0.71 [1.7] -1.01 (-0.33mmol/L) [-1.5 to -0.6]; Secondary outcomes Change from week 12 to 16 (or LOCF) in mean [SD] serum levels of: Calcium, mg/dl 0.05 [0.7] -0.09 [0.5] 0.13 [-0.04 to 0.3]; p=0.136 CaxP ion product, mg 2 /dl 2-0.2 [13.4] 5.7 [14.6] -7.9 [-11.8 to -4.0]; Parathyroid hormone, pg/ml -6.2 [234.5] 61.8 [146.4] -66.6 [-119.4 to -13.7]: p=0.014 LDL-cholesterol, % change 4.0 [25.0] 56.4 [46.1] -51.9 [-62.5 to -41.3]; Total cholesterol, % change 2.8 [24.7] 26.4 [22.7] -23.0 [-30.1 to -16.0]; Proportion of responders (with serum level 5.5mg/dL or 1.78mmol/L) at: Week 12, % 45.2 42.2 Week 16, % 51.2 20.5 Change from baseline to week 12 (or LOCF) in mean [SD] serum levels of: Phosphate, mg/dl -1.54 [2.1] (-0.5mmol/L) <0.001 p value vs. baseline Calcium, mg/dl 0.02 [0.8] t significant CaxP ion product, mg 2 /dl 2-13.0 [18.0] <0.001 Parathyroid hormone, pg/ml -33.6 [187.7] 0.006 LDL-cholesterol, % change -30.1 [21.6] <0.001 Abbreviations CaxP calcium x ; CI confidence interval; ITT intention-to-treat; LDL low-density lipoprotein; LOCF last observation carried forward; $ LS least squares; OR odds ratio; SD standard deviation. te $ LS mean provides a more accurate estimate of the true mean by taking account of imbalances between groups in baseline levels, given, and study centre.
Trial design Placebo $ LS mean difference [95% CI] E07 11) Double-blind, flexible-dose, (69), withdrawal PIII trial. The study consisted of: a 4 week washout period for current binders, a 12-week open-label flexibledose titration period with patients 1:1 to colestilan or sevelamer, and a 4-week doubleblind, placebo controlled withdrawal period comparing colestilan and placebo. Men or women aged 18 years with CKD5. Serum 1.94mmol/L and 15% rise after two and three weeks of washout, or 2.58mmol/L and 15% rise after one week of washout. Haemodialysis or peritoneal dialysis. Stable low diet. Stable levels on binders 1 month. Constant calcium dialysate. Clinically significant co-morbidities, incl. liver dysfunction and gastrointestinal motility disorders. Serum albumin <30g/dL or ipth consistently or frequently >1,000pg/mL. Body mass index 16kg/m 2 or 40kg/m 2. Phosphate level >2.97mmol/L during periods. Open-label, active controlled period (baseline to week 12): 336 patients. ITT population, n=327. Safety population, n=331 (205 men), mean age 58 years (range 19 to 89). 68% previously on one binder and 32% previously on >one binder. Patients started on: colestilan 6g/day and titrated up or down by 3g/day every three weeks to maximum 15g/day, OR sevelamer 2.4g/day if 2.42mmol/L, or 4.8g/day if >2.42mmol/L, and titrated up or down by 2.4g/day every three weeks to maximum 12g/day, until serum between 1.13 and 1.78mmol/L. Double-blind period (week 12 to 16): 104 patients on colestilan re, 50 colestilan, 54 placebo. ITT population, n=103. Patients on colestilan maintained on same dose they were taking at the end of flexible-dose period. Baseline data Mean levels at baseline (mmol/l): Phosphate 2.22 colestilan group, 2.36 sevelamer group. Calcium 2.17 colestilan group, 2.19 sevelamer group. Primary outcome. Change from week 12 to 16 (or LOCF) in mean [SD] serum levels of: Phosphate, mmol/l -0.08 [0.5] 0.41 [0.5] -0.43 [-0.6 to -0.3]; Secondary outcomes Change from week 12 to 16 (or LOCF) in mean [SD] serum levels of: Calcium, mmol/l -0.002 [0.1] -0.023 [0.1] 0.03 [-0.02 to 0.08]; p=0.307 CaxP ion product, mmol 2 /L 2-0.2 [1.0] 0.9 [1.1] -0.9 [-1.3 to -0.5]; ipth, pmol/l 2.6 [18.6] 9.9 [12.2] -7.1 [-13.5 to -0.7]; p= 0.03 LDL-cholesterol, % change 9.3 [24.6] 82.0 [65.1] -71.7 [-90.3 to -53.2]; Total cholesterol, % change 4.8 [17.2] 39.5 [28.9] -35.1 [-44.3 to -26.0]; Proportion of responders (with serum level 1.78mmol/L) at week 16 Number (%) vs. placebo 23 (46.0) 12 (23.1) OR 2.95 [1.2 to 7.6]; p=0.025 Sevelamer LS mean difference [95% CI] Change from baseline to week 12 (or LOCF) in mean [SD] serum levels of: Phosphate, mmol/l -0.36 [0.5] -0.70 [0.5] 0.29 [0.2 to 0.4]; p=nr, noninferiority could not be concluded. Calcium, mmol/l -0.04 [0.1] 0.03 [0.2] -0.06 [-0.09 to -0.03]; CaxP ion product, mmol 2 /L 2-0.9 [0.2] -1.5 [1.1] 0.5 [0.3 to 0.8]; ipth, pmol/l -3.6 [18.5] -7.2 [18.5] 2.5 [-1.4 to 6.3]; p=0.209 LDL-cholesterol, % change -35.3 [19.5] -30.5 [20.3] -5.1 [-9.4 to -0.7]; p=0.023 Total cholesterol, % change -24.2 [14.1] -17.7 [17.5] -6.8 [-10.3 to -3.3]; Proportion of responders (serum level 1.78mmol/L) at week 12 Number (%) vs. sevelamer 65 (42.5) 111 (67.7) OR 0.29 [0.2 to 0.5]; Abbreviations CaxP calcium x ; CI confidence interval; CKD5 chronic kidney disease stage 5; ipth intact parathyroid hormone; ITT intention-to-treat; LDL low-density lipoprotein; LOCF last observation carried forward; $ LS least squares; NR not reported; OR odds ratio; SD standard deviation. te 1 $ LS mean provides a more accurate estimate of the true mean by taking account of imbalances between groups in baseline levels, given, and study centre.
Table 2. Fixed-dose trial. Trial design Placebo $ LS mean difference [95% CI] E08 10) Double-blind, fixed-dose, (100), PIII trial. The study consisted of: a washout period (8 weeks for lipid lowering drugs and 4 weeks for binders), a 12-week double-blind, fixed-dose period with patients to colestilan 1g tablets or matching placebo. Power calculation: 54 patients needed per group to show a difference between colestilan and placebo in change of serum 0.4mmol/L Patients aged 18 years with chronic kidney disease stage 5. Serum 1.94mmol/L and 15% rise at baseline after washout of binders, or 2.58mmol/L and 15% rise at any time during weeks -4 to baseline during washout. Serum LDLcholesterol 1.82mmol/L. Haemodialysis or peritoneal dialysis. Stable low diet. Concomitant use of lipid or affecting drugs. During the doubleblind period, serum >2.97mmol/L during weeks 1 to 4, >2.58mmol/L during weeks 5 to 12, or <0.97mmol/L at any time. LDL-cholesterol >4.94mmol/L. 642 patients, (53% men), mean age 49 years (range 19 to 80). ITT population, n=631. Patients were to one of the following groups: colestilan 3g (3 tablets/day) plus 6 placebo tablets (n=104), colestilan 6g (6 tablets/day) plus 3 placebo tablets (n=101), colestilan 9g (9 tablets/day) (n=97), placebo 9 tablets/day (n=77), colestilan 12g (12 tablets/day) (n=100), placebo 12 tablets/day (n=27), colestilan 15g (15 tablets/day) (n=99), placebo 15 tablets/day (n=26). Patients in the 12g and 15g groups were pooled for analysis in order to limit the number of patients required, as the inclusion/exclusion criteria were expected to affect recruitment to the study. Baseline data Mean (SD) serum (in mg/dl) after washout: colestilan 3g, 7.32 (1.4), Primary outcomes. Change from baseline to week 12 (or LOCF) in mean [SD] serum levels of: Phosphate, mg/dl 3g -0.23 [1.6] LDL-cholesterol, % change Secondary outcomes -0.07 [-0.54 to 0.41]; p=0.785 6g -0.77 [2.0] 9 tabs -0.15 [1.7] -0.52 [-1.00 to -0.03]; p=0.036 9g -0.97 [1.7] -0.66 [-1.16 to -0.16]; p=0.009 12g -0.71 [1.8] Pooled 15g -1.41 [1.4] 15 tabs 3g -16.7 [20.1] -0.12 [1.7] -0.88 (-0.3mmol/L) [-1.22 to -0.54]; -17.8 [-23.5 to -12.0]; 6g -23.6 [21.0] 9 tabs 1.5 [16.3] -25.5 [-31.3 to -19.7]; 9g -27.6 [21.5] -29.5 [-35.4 to -23.5]; 12g -29.4 [25.3] Pooled 15g -27.5 [24.6] 15 tabs Change from baseline to week 12 in mean [SD] serum levels of: 2.8 [17.4] -31.7 [-36.5 to -26.9]; Calcium, mmol/l 3g -0.023 [0.1] 0.02 [-0.02 to 0.07]; p=0.38 6g -0.006 [0.2] 9 tabs -0.039 [0.1] 0.03 [-0.01 to 0.08]; p=0.174 9g -0.046 [0.2] -0.01 [-0.05 to 0.04]; p=0.816 Calcium x ion product, mmol 2 /L 2 12g -0.022 [0.2] Pooled 15g -0.01 [0.2] 15 tabs 3g -0.2 [1.2] -0.022 [0.2] 0.00 [-0.04 to 0.03]; p=0.863-0.02 [-0.3 to 0.4]; p=0.891 6g -0.6 [1.5] 9 tabs -0.2 [1.2] -0.3 [-0.7 to 0.1]; p=0.109 9g -0.8 [1.2] -0.5 [-0.9 to -0.1]; p=0.011 12g -0.5 [1.3] Pooled 15g -1.0 [1.1] 15 tabs -0.1 [1.3] -0.6 [-0.9 to -0.4];
Trial design Placebo $ LS mean difference [95% CI] (1.2mg/dL) and serum LDLcholesterol 30% (with 90% power and 5% significance level, assuming 10% drop-out rate). Serum triglycerides >6.76mmol/L. Serum albumin <30g/L or *ipth persistently >1,000pg/mL. Significant gastrointestinal abnormalities or liver dysfunction. colestilan 6g, 7.53 (1.4), colestilan 9g, 7.61 (1.5), placebo 9 tablets/day, 7.30 (1.4), colestilan 12g+15g, 7.23 (1.5), pooled placebo (15 tablets/day), 7.20 (1.5). Baseline mean serum LDLcholesterol was 2.9mmol/L. Intact parathyroid hormone, pmol/l Total cholesterol, % change 3g 3.6 [38.9] 1.6 [-8.0 to 11.2]; p=0.74 6g 0.01 [20.6] 9 tabs 2.4 [24.8] -2.2 [-11.8 to 7.5]; p=0.658 9g -5.1 [42.7] -7.1 [-17.0 to 2.9]; p=0.163 12g 0.8 [20.7] Pooled 15g -1.9 [46.2] 15 tabs 3g -10.5 [14.5] 2.5 [23.1] -3.7 [-10.7 to 3.2]; p=0.293-12.3 [-16.4 to -8.1]; 6g -15.5 [15.1] 9 tabs 2.2 [12.8] -17.9 [-22.0 to -13.7]; Previous medication Nearly all patients had received a binder. 11.4% of patients had received lipid-lowering drugs (usually a statin). Glycosylated haemoglobin A1c, % 9g -20.8 [14.1] -22.7 [-27.0 to -18.5]; 12g -22.2 [16.7] Pooled 15g -20.5 [19.1] 15 tabs 3g -0.07 [0.5] 3.2 [13.0] -24.6 [-28.1 to -21.2]; -0.15 [-0.31 to 0.02]; p=0.078 6g -0.13 [0.7] 9 tabs 0.10 [0.4] -0.21 [-0.38 to -0.05]; p=0.011 Compliance data Compliance was defined as taking 80-120% of study medication. 88-90% of patients in the colestilan 3, 6 and 9g groups were compliant vs. 91% in the placebo 9 tablets/day group. 84% of patients in the 12g group were compliant vs. 91.5% in the pooled placebo group. 74.5% of patients in the 15g group were compliant vs. 91.5% in the pooled placebo group. 9g -0.13 [0.6] -0.21 [-0.38 to -0.04]; P=0.014 12g -0.19 [0.7] Pooled 15g -0.24 [0.6] 15 tabs 0.06 [0.4] -0.27 [-0.40 to -0.13]; Proportion of responders (with serum level 5.5mg/dL or 1.78mmol/L) (LOCF) at week 12 Number (%) 3g 21 (20.4) OR 1.03 [0.48 to 2.20]; p=0.948 6g 21 (21.0) 9 tabs 15 (19.7) OR 1.17 [0.55 to 2.51]; p=0.686 9g 25 (28.7) OR 1.93 [0.90 to 4.12]; p=0.09 12g 28 (30.1) 15g 32 (36.4) Pooled 12+15 tablets 26 (20.2) OR 2.15 [1.23 to 3.77]; p=0.007 Abbreviations CaxP calcium x ; CI confidence interval; ITT intention-to-treat; LDL low-density lipoprotein; LOCF last observation carried forward; $ L S least squares; OR odds ratio; SD standard deviation. te 1 $ LS mean provides a more accurate estimate of the true mean by taking account of imbalances between groups in baseline levels, given, and study centre.
Table 3. Long-term trials. Trial Design Mean difference [95% CI] A06 13) Open-label, flexibledose, (23) PIII trial. The study consisted of: a 2-6 week washout period for current binders, a 52-week openlabel, flexibledose period. Chronic kidney disease stage 5. Serum 5.6mg/dL and 15% rise after washout of binders, or 8mg/dL and 15% rise at any time during washout. Dialysis type not stated. t available. 116 patients (76 men) enrolled, mean age 57 years (range 18 to 85). All patients started on colestilan 6g/day and titrated up or down to maximum 15g/day, to maintain serum levels between 3.5mg/dL and 5.5mg/dL (1.13 and 1.78mmol/L). 11% stopped colestilan due to AEs week 12 and 13% > week 12. Change from baseline to week 52 (or LOCF) in mean [CI] serum levels of: Phosphate, mg/dl 6.99 (2.26mmol/L) at baseline to 5.80 (1.87mmol/L) at week 52-1.18 (-0.38mmol/L) [-1.56 to -0.81]; Calcium, mg/dl Calcium x ion product, mg 2 /dl 2 Parathyroid hormone, pg/ml LDL-cholesterol, % change Total cholesterol, % change Glycosylated haemoglobin A1c, % 0.08 [-0.06 to 0.21]; p=0.278-10.0 [-13.3 to -6.7]; -33.9 [-85.3 to 17.5]; p=0.194-24.0 [-29.0 to -18.9]; -14.3 [-17.9 to -10.6]; -0.19 [-0.36 to -0.02]; p=0.026 E10 11) Open-label, flexibledose, (128) PIII trial. The study was an extension of studies E07, E08 and E09 (which lasted 12-16 weeks). It consisted of a 40-week openlabel, flexible-dose period. te: Data for colestilan patients enrolled in E07 presented separately, and combined with other patients enrolled in E10. Patients completing studies E07, E08 and E09. See E07 and E08 above (not available for E09). See E07 and E08 above (not available for E09). 556 patients (300 men) enrolled, mean age 52 years (range 19 to 88). All patients on colestilan started on 6g/day (regardless of previous dose) to maintain blinding; patients on sevelamer stayed on the same dose as at the end of study E07. Patients were titrated up or down to maximum colestilan 15g/day or sevelamer 12g/day, to maintain serum levels 1.78mmol/L. Baseline data See studies E07 and E08 above. Nil for E09. E10 study (n=429) E07 study (n=75) Change from baseline to week 52 (or LOCF) in mean [CI] serum levels of: Phosphate, mg/dl -1.23 (-0.41mmol/L) [-1.4 to -1.1]; Calcium, mmol/l -0.022 [-0.04 to 0.00]; p=0.015 Calcium x ion product, mmol 2 /L 2-0.9 [-1.1 to -0.8]; Intact parathyroid hormone, pmol/l LDL-cholesterol, % change 9.4 [4.3 to 14.5]; -26.2 [-28.8 to -23.7]; -1.47 (-0.49mmol/L) [-1.9 to -1.1]; -0.02 [-0.1 to 0.03]; p=0.392-1.1 [-1.3 to -0.8]; 7.1 [0.8 to 13.4]; p=0.029-30.6 [-35.3 to -26.0]; Sevelamer (n=124) -2.26 (-0.75mmol/L) [-2.6 to -1.9]; 0.035 [0.00 to 0.07]; p=0.053-1.5 [-1.8 to -1.3]; 0.9 [-4.8 to 6.7]; p=0.747-28.7 [-32.9 to -24.5]; Proportion of responders (with serum level 5.5mg/dL or 1.78mmol/L) at week 40 Number (%) 183 (42.7) 49 (65.3) 83 (66.9) Abbreviations AE adverse effects; CI confidence interval; LDL low-density lipoprotein; LOCF last observation carried forward.