ePHex: a phase 3, double-blind, placebo-controlled, randomized study to evaluate long-term efficacy and safety of Oxalobacter formigenes in patients with primary hyperoxaluria.

BACKGROUND: Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration. Oxalobacter formigenes is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized O. formigenes formulation, at reducing plasma oxalate levels in patients suffering from PH. METHODS: Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m2) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint. RESULTS: Forty-three subjects were screened, 25 were recruited and one was discontinued. At Week 52, O. formigenes was established in the gut of subjects receiving Oxabact. Despite decreasing plasma oxalate level in subjects treated with Oxabact, and stable/increased levels with placebo, there was no significant difference between groups in the primary outcome (Least Squares mean estimate of treatment difference was - 3.80 µmol/L; 95% CI: - 7.83, 0.23; p-value = 0.064). Kidney function remained stable in both treatments. CONCLUSIONS: Oxabact treatment may have stabilized/reduced plasma oxalate versus a rise with placebo, but the difference over 12 months was not statistically significant (p = 0.06). A subtle effect observed with Oxabact suggests that O. formigenes may aid in preventing kidney stones. A higher resolution version of the Graphical abstract is available as Supplementary information.

Natural History of Clinical, Laboratory, and Echocardiographic Parameters of a Primary Hyperoxaluria Cohort on Long Term Hemodialysis.

Background: Primary hyperoxaluria type 1 (PH1) is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage, often requiring renal replacement therapy (RRT). Though systemic oxalate deposition is well-known, the natural history of PH1 during RRT has not been systematically described. In this study, we describe the clinical, laboratory, and echocardiographic features of a cohort of PH1 patients on RRT. Methods: Patients with PH1 enrolled in the Rare Kidney Stone Consortium PH Registry who progressed to require RRT, had ≥2 plasma oxalate (pOx) measurements 3-36 months after start of RRT, and at least one pair of pOx measurements between 6 and 18 months apart were retrospectively analyzed. Clinical, echocardiographic, and laboratory results were obtained from the Registry. Results: The 17 PH1 patients in our cohort had a mean total HD hours/week of 17.4 (SD 7.9; range 7.5-36) and a range of age of RRT start of 0.2-75.9 years. The average change in plasma oxalate (pOx) over time on RRT was -0.74 [-2.9, 1.4] µmol/L/month with the mean pOx never declining below 50 µmol/L. Over time on RRT, oxalosis progressively developed in multiple organ systems. Echocardiography performed on 13 subjects showed worsening of left ventricular global longitudinal strain correlated with pOx (p < 0.05). Conclusions: Even when a cohort of PH1 patients were treated with intensified RRT, their predialysis pOx remained above target and they developed increasing evidence of oxalosis. Echocardiographic data suggest that cardiac dysfunction could be related to elevated pOx and may worsen over time.

Plasma oxalate and eGFR are correlated in primary hyperoxaluria patients with maintained kidney function-data from three placebo-controlled studies.

BACKGROUND: In patients with primary hyperoxaluria (PH), endogenous oxalate overproduction increases urinary oxalate excretion, leading to compromised kidney function and often kidney failure. Highly elevated plasma oxalate (Pox) is associated with systemic oxalate deposition in patients with PH and severe chronic kidney disease (CKD). The relationship between Pox and estimated glomerular filtration rate (eGFR) in patients with preserved kidney function, however, is not well established. Our analysis aimed to investigate a potential correlation between these parameters in PH patients from three randomized, placebo-controlled trials (studies OC3-DB-01, OC3-DB-02, and OC5-DB-01). METHODS: Baseline data from patients with a PH diagnosis (type 1, 2, or 3) and eGFR > 40 mL/min/1.73 m2 were analyzed for a correlation between eGFR and Pox using Spearman's rank and Pearson's correlation coefficients. Data were analyzed by individual study and additionally were pooled for Studies OC3-DB-02 and OC5-DB-01 in which the same Pox assay was used. RESULTS: A total of 106 patients were analyzed. A statistically significant inverse Spearman's correlation between eGFR and Pox was observed across all analyses; correlation coefficients were - 0.44 in study OC3-DB-01, - 0.55 in study OC3-DB-02, - 0.51 in study OC5-DB-01, and - 0.49 in the pooled studies (p < 0.0064). CONCLUSIONS: Baseline evaluations showed a moderate and statistically significant inverse correlation between eGFR and Pox in patients with PH already at early stages of CKD (stages 1-3b), demonstrating that a correlation is present before substantial loss in kidney function occurs.

Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria Type 1 and end-stage renal disease: a Phase II study.

BACKGROUND: In primary hyperoxaluria Type 1 (PH1), endogenous oxalate overproduction significantly elevates urinary oxalate excretion, resulting in recurrent urolithiasis and/or progressive nephrocalcinosis and often early end-stage renal disease (ESRD). In ESRD, dialysis cannot sufficiently remove oxalate; plasma oxalate (Pox) increases markedly, inducing systemic oxalate deposition (oxalosis) and often death. Interventions to reduce Pox in PH1 subjects with ESRD could have significant clinical impact. This ongoing Phase II, open-label trial aimed to evaluate whether long-term Oxabact™ (Oxalobacter formigenes, OC5, OxThera Intellectual Property AB, Sweden) lowers Pox in PH1 ESRD subjects, ameliorating clinical outcome. METHODS: PH1 ESRD subjects on stable dialysis regimens were examined. Subjects were administered one OC5 capsule twice daily for up to 36 months or until transplantation. Total Pox values, cardiac function and safety were evaluated. Free Pox was evaluated in a comparative non-treated PH1 dialysis group using retrospective chart reviews and analyses. RESULTS: Twelve subjects enrolled in an initial 6-week treatment phase. Following a washout of up to 4 weeks, eight subjects entered a continuation study; outcomes after 24 months of treatment are presented. After 24 months, all subjects had reduced or non-elevated Pox compared with baseline. Cardiac function improved, then stabilized. No treatment-related serious adverse events were reported. CONCLUSIONS: Compared with an untreated natural control cohort, 24 months OC5 administration was beneficial to PH1 ESRD subjects by substantially decreasing Pox concentrations, and improving or stabilizing cardiac function and clinical status, without increasing dialysis frequency. OC5 was safe and well-tolerated.

End Points for Clinical Trials in Primary Hyperoxaluria.

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.

An open-label, single-dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinacalcet in pediatric subjects aged 28 days to < 6 years with chronic kidney disease receiving dialysis.

BACKGROUND: Calcimimetics, shown to control biochemical parameters of secondary hyperparathyroidism (SHPT), have well-established safety and pharmacokinetic profiles in adult end-stage renal disease subjects treated with dialysis; however, such studies are limited in pediatric subjects. METHODS: In this study, the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cinacalcet were evaluated in children with chronic kidney disease (CKD) and SHPT receiving dialysis. Twelve subjects received a single dose of cinacalcet (0.25 mg/kg) orally or by nasogastric or gastric tube. Subjects were randomized to one of two parathyroid hormone (PTH) and serum calcium sampling sequences: [(1) 2, 8, 48 h; or (2) 2, 12, 48 h] and assessed for 72 h after dosing. RESULTS: Median plasma cinacalcet tmax was 1 h (range 0.5-4.0 h); mean (SD) Cmax and AUClast were 2.83 (1.98) ng/mL and 11.8 (8.74) h*ng/mL, respectively; mean (SD) half-life (t1/2) was 3.70 (2.57) h. Dose adjustments, based upon body weight (mg/kg), minimized the effects of age, body weight, body surface area, and body mass index on cinacalcet PK. Reductions in serum PTH levels from baseline were observed at 2 to 8 h post-dose (median 10.8 and 29.6%, respectively), returned towards baseline by 12-72 h and were inversely related to changes in the plasma cinacalcet PK profile. Single-dose cinacalcet was well-tolerated with no unexpected safety findings and a PK/PD, safety profile similar to adults. CONCLUSIONS: In conclusion, a single 0.25 mg/kg dose of cinacalcet was evaluated to be a safe starting dose in these children aged < 6 years.

Correction to: An open-label, single-dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cinacalcet in pediatric subjects aged 28 days to < 6 years with chronic kidney disease receiving dialysis.

The original version of this article unfortunately contained three mistakes. In Table 1, the last line under "Key Inclusion Criteria" should read "Normal or clinically acceptable ECGs at screening and at day - 1." In addition, the abbreviation "IP" in the legend to Table 1 stands for "investigational product."

A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet in pediatric patients with chronic kidney disease and secondary hyperparathyroidism receiving dialysis.

BACKGROUND: This randomized phase 3 study evaluated the efficacy and safety of cinacalcet in children with secondary hyperparathyroidism (SHPT) receiving dialysis. METHODS: This study had double-blind and open-label phases. Eligible patients aged 6-< 18 years were randomized to cinacalcet (starting dose ≤ 0.20 mg/kg) or placebo. The primary endpoint was ≥ 30% reduction from baseline in mean intact parathyroid hormone (iPTH). Secondary endpoints included mean iPTH ≤ 300 pg/mL; percentage change from baseline in corrected total serum calcium, phosphorus, and calcium phosphorus product (Ca × P); and safety. RESULTS: The double-blind phase comprised 43 patients (cinacalcet, n = 22; placebo, n = 21). Nineteen months into the study, regulatory authorities were notified of a fatality; the study was subsequently terminated after a 14-month clinical hold. Before the hold, 12 patients (55%) on cinacalcet and four (19%) on placebo achieved the primary endpoint (p = 0.017), and 27% and 24%, respectively, achieved iPTH ≤ 300 pg/mL. The between-group differences (95% CI) in percentage changes for total serum calcium, phosphorus, and Ca × P were - 4% (- 9 to 1%), - 6% (- 21 to 8%), and - 10% (- 23 to 3%). The mean maximum actual weight-adjusted daily cinacalcet dosage administered was 0.99 mg/kg/day. Overall, 82% of patients on cinacalcet and 86% on placebo had ≥ 1 treatment-emergent adverse event; the most common were vomiting (32%, 24%, respectively), hypocalcemia (23%, 19%), nausea (18%, 14%), and hypertension (14%, 24%). CONCLUSIONS: Despite early termination, efficacy and safety outcomes observed with cinacalcet in children with SHPT on dialysis were consistent with adult observations, suggesting cinacalcet may meet an unmet medical need for this population.

A Decision-Analytic Model to Assess the Cost-Effectiveness of Etelcalcetide vs. Cinacalcet.

INTRODUCTION: Etelcalcetide is a novel intravenous calcimimetic for the treatment of secondary hyperparathyroidism (SHPT) in haemodialysis patients. The clinical efficacy and safety of etelcalcetide (in addition to phosphate binders and vitamin D and/or analogues [PB/VD]) was evaluated in three phase III studies, including two placebo-controlled trials and a head-to-head study versus the oral calcimimetic cinacalcet. OBJECTIVE: The objective of this study was to develop a decision-analytic model for economic evaluation of etelcalcetide compared with cinacalcet. METHODS: We developed a life-time Markov model including potential treatment effects on mortality, cardiovascular events, fractures, and subjects' persistence. Long-term efficacy of etelcalcetide was extrapolated from the reduction in parathyroid hormone (PTH) in the phase III trials and the available data from the outcomes study in cinacalcet (EVOLVE trial). Etelcalcetide was compared with cinacalcet, both in addition to PB/VD. We applied unit costs averaged from five European countries and a range of potential etelcalcetide pricing options assuming parity price to weekly use of cinacalcet and varying it by a 15 or 30% increase. RESULTS: Compared with cinacalcet, the incremental cost-effectiveness ratio of etelcalcetide was €1,355 per QALY, €24,521 per QALY, and €47,687 per QALY for the three prices explored. The results were robust across the probabilistic and deterministic sensitivity analyses. CONCLUSIONS: Our modelling approach enabled cost-utility assessment of the novel therapy for SHPT based on the observed and extrapolated data. This model can be used for local adaptations in the context of reimbursement assessment.

Enhancing clinical trial development for pediatric kidney diseases.

The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the small number of appropriate patients available for such studies. The American Society of Pediatric Nephrology Therapeutics Development Committee (TDC) was established to (1) identify the various stakeholders with interests and/or expertise related to clinical trials in children with kidney disease and (2) develop more effective partnerships among all parties regarding strategies for successful clinical trial development and execution. This article discusses the rationale, structure, and function of the TDC, the status of progress toward its goals, and the insights gained to date that may be useful for other subspecialties that face similar challenges.

Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial.

Importance: Secondary hyperparathyroidism contributes to extraskeletal calcification and is associated with all-cause and cardiovascular mortality. Control is suboptimal in the majority of patients receiving hemodialysis. An intravenously (IV) administered calcimimetic could improve adherence and reduce adverse gastrointestinal effects. Objective: To evaluate the relative efficacy and safety of the IV calcimimetic etelcalcetide and the oral calcimimetic cinacalcet. Design, Setting, and Participants: A randomized, double-blind, double-dummy active clinical trial was conducted comparing IV etelcalcetide vs oral placebo and oral cinacalcet vs IV placebo in 683 patients receiving hemodialysis with serum parathyroid hormone (PTH) concentrations higher than 500 pg/mL on active therapy at 164 sites in the United States, Canada, Europe, Russia, and New Zealand. Patients were enrolled from August 2013 to May 2014, with end of follow-up in January 2015. Interventions: Etelcalcetide intravenously and oral placebo (n = 340) or oral cinacalcet and IV placebo (n = 343) for 26 weeks. The IV study drug was administered 3 times weekly with hemodialysis; the oral study drug was administered daily. Main Outcomes and Measures: The primary efficacy end point was noninferiority of etelcalcetide at achieving more than a 30% reduction from baseline in mean predialysis PTH concentrations during weeks 20-27 (noninferiority margin, 12.0%). Secondary end points included superiority in achieving biochemical end points (>50% and >30% reduction in PTH) and self-reported nausea or vomiting. Results: The mean (SD) age of the trial participants was 54.7 (14.1) years and 56.2% were men. Etelcalcetide was noninferior to cinacalcet on the primary end point. The estimated difference in proportions of patients achieving reduction in PTH concentrations of more than 30% between the 198 of 343 patients (57.7%) randomized to receive cinacalcet and the 232 of 340 patients (68.2%) randomized to receive etelcalcetide was -10.5% (95% CI, -17.5% to -3.5%, P for noninferiority, <.001; P for superiority, .004). One hundred seventy-eight patients (52.4%) randomized to etelcalcetide achieved more than 50% reduction in PTH concentrations compared with 138 patients (40.2%) randomized to cinacalcet (P = .001; difference in proportions, 12.2%; 95% CI, 4.7% to 19.5%). The most common adverse effect was decreased blood calcium (68.9% vs 59.8%). Conclusions and Relevance: Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, the use of etelcalcetide was not inferior to cinacalcet in reducing serum PTH concentrations over 26 weeks; it also met superiority criteria. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT1896232.

Analyzing Health-Related Quality of Life in the EVOLVE Trial: The Joint Impact of Treatment and Clinical Events.

BACKGROUND: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) clinical trial evaluated the effects of cinacalcet on clinical events in patients with secondary hyperparathyroidism (sHPT) who were on hemodialysis. Health-related quality of life (HRQoL) was assessed by a generic, preference-based health outcome measure (EQ-5D) at scheduled visits and after a study event. Here, we report the HRQoL analysis from EVOLVE. METHODS: We assessed changes in HRQoL from baseline to scheduled visits, and estimated the acute (3 mo) and chronic (beyond 3 mo) effects of sHPT-related events on HRQoL using generalized estimating equation analysis controlling for baseline HRQoL and randomized assignment. RESULTS: Data on HRQoL were available for 3547 of 3883 subjects, with 1650 events in the placebo and 1502 in the cinacalcet arm. At the study end, no difference in change from baseline HRQoL was observed in the direct comparison of EQ-5D by treatment arms. The regression analysis showed significant effects of events on HRQoL and a modest positive effect of cinacalcet. Estimated quality-adjusted life-year gains were of similar magnitude based on the observed data or the predictions from the model, with only a small gain in precision from the predicted analysis. CONCLUSIONS: By contrast with a conventional comparison, a regression analysis demonstrated large decrements in HRQoL after events and a modest improvement in HRQoL with cinacalcet. As randomized controlled trials are rarely powered to detect differences in HRQoL, a prespecified regression analysis may be acceptable to improve precision of the effects and understand their origin.

Cinacalcet, dialysate calcium concentration, and cardiovascular events in the EVOLVE trial.

Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.

Economic Evaluation of Cinacalcet in the United States: The EVOLVE Trial.

BACKGROUND: Previous economic evaluations of cinacalcet in patients with secondary hyperparathyroidism (sHPT) relied on the combination of surrogate end points in clinical trials and epidemiologic studies. OBJECTIVES: The objective was to conduct an economic evaluation of cinacalcet on the basis of the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial from a US payer perspective. METHODS: We developed a semi-Markov model to assess the cost-effectiveness of cinacalcet in addition to conventional therapy, compared with conventional therapy alone, in patients with moderate-to-severe sHPT receiving hemodialysis. We used treatment effect estimates from the unadjusted intent-to-treat (ITT) analysis and prespecified covariate-adjusted ITT analysis as our main analyses. We assessed model sensitivity to variations in individual inputs and overall decision uncertainty through probabilistic sensitivity analyses. RESULTS: The incremental cost-effectiveness ratio (ICER) for cinacalcet was $61,705 per life-year and $79,562 per quality-adjusted life-year (QALY) gained using the covariate-adjusted ITT analysis. Probabilistic sensitivity analysis suggested a 73.2% chance of the ICER being below a willingness-to-pay threshold of $100,000. Treatment effects from unadjusted ITT analysis yielded an ICER of $115,876 per QALY. The model was most sensitive to the treatment effect on mortality. CONCLUSIONS: In the unadjusted ITT analysis, cinacalcet does not represent a cost- effective use of health care resources when applying a willingness-to-pay threshold of $100,000 per QALY. When using the covariate-adjusted ITT treatment effect, which represents the least biased estimate, however, cinacalcet is a cost-effective therapy for patients with moderate-to-severe sHPT on hemodialysis.

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial.

BACKGROUND: Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. METHODS AND RESULTS: This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS: Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

Assessing the treatment effect in a randomized controlled trial with extensive non-adherence: the EVOLVE trial.

Intention-to-treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long-term outcomes study where non-adherence to study drug is substantial, the on-treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double-blind, placebo-controlled, event-driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre-specified sensitivity analyses were performed to assess the impact of non-adherence on the estimated effect of cinacalcet. These analyses included lag-censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag-censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on-treatment effect when substantial non-adherence to study drug is expected or observed.

The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial.

BACKGROUND AND OBJECTIVES: The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. RESULTS: Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. CONCLUSIONS: In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial.

Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial.

BACKGROUND: Premature cardiovascular disease limits the duration and quality of life on long-term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial. METHODS AND RESULTS: EVOLVE was a randomized, double-blind, placebo-controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance. CONCLUSIONS: Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes. CLINICAL TRIALS REGISTRATION: Unique identifier: NCT00345839. URL: ClinicalTrials.gov.