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Pediatric Nephrology

, Volume 34, Issue 3, pp 475–486 | Cite as

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

  • Bradley A. WaradyEmail author
  • Janet N. Iles
  • Gema Ariceta
  • Bastian Dehmel
  • Guillermo Hidalgo
  • Xun Jiang
  • Benjamin Laskin
  • Shahnaz Shahinfar
  • Johan Vande Walle
  • Franz Schaefer
Original Article
Part of the following topical collections:
  1. What’s New in Chronic Kidney Disease

Abstract

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.

Keywords

Calcimimetics Chronic kidney disease Cinacalcet Parathyroid hormone Pediatric patients Secondary hyperparathyroidism 

Introduction

Secondary hyperparathyroidism (SHPT) is a common and serious comorbidity that can develop early in the course of chronic kidney disease (CKD), often worsens with declining kidney function, and is associated with serious complications in adults and children receiving dialysis [1, 2]. Such children receiving dialysis can experience a wide spectrum of bone abnormalities and growth retardation [2, 3, 4] and are at increased risk of cardiovascular morbidity and mortality that manifests early in their adulthood [5]. Traditional therapies for SHPT (e.g., vitamin D sterols) are widely used in the pediatric dialysis population, although they are frequently ineffective and have the potential to aggravate complications of the disease by increasing serum calcium, serum phosphorus, and the calcium phosphorus product (Ca × P) [6].

Cinacalcet is a first-in-class calcimimetic that is indicated for the treatment of SHPT in adult patients with CKD receiving dialysis [7]. The safety and efficacy of cinacalcet in adults with CKD and SHPT receiving dialysis have been extensively investigated and reviewed [8, 9]. The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline update on CKD-mineral and bone disorder suggests the use of calcimimetics, calcitriol, vitamin D analogs, or a combination thereof in patients with stage 5 CKD receiving dialysis who require parathyroid hormone (PTH)-lowering therapy [10]. However, safety and efficacy data for cinacalcet are currently lacking in the pediatric end-stage renal disease population because previous results have been limited to small, single-center, retrospective or prospective observational studies and case reports [11, 12, 13, 14]. This prospective, double-blind, placebo-controlled study was conducted to evaluate the efficacy of cinacalcet for reducing plasma intact PTH (iPTH), the effect of cinacalcet on calcium and phosphorus, and the safety and tolerability of cinacalcet in pediatric patients with SHPT receiving dialysis.

Methods

Patients

Patients were eligible if they were aged 6 to < 18 years with CKD and SHPT (iPTH levels > 300 pg/mL at screening by central laboratory), treated with hemodialysis or peritoneal dialysis for ≥ 2 months before randomization, and had corrected serum calcium ≥ 8.8 mg/dL and serum phosphorus ≥ 4.0 mg/dL if aged 6 to < 12 years or ≥ 3.5 mg/dL if aged 12 to < 18 years. For patients already receiving vitamin D sterols (calcitriol or a synthetic analog), the dose had to be stable within the preceding 2 months before randomization; for those taking recombinant growth hormone, the dose could not have been changed by > 20% within the preceding 2 months. Patients were excluded if they had a parathyroidectomy within 6 months before or anticipated having one within 6 months after randomization, if they were scheduled for a kidney transplant from a living donor that would make study completion unlikely, or if they had received cinacalcet within 1 month before randomization. The study protocol was approved by the institutional review board or independent ethics committee of each study center. Before a patient was permitted to participate in the clinical study, the investigator was responsible for obtaining written informed consent from every patient’s parent or legally acceptable representative. In accordance with local laws, the institutional review board or independent ethics committee may also have required the patient’s assent from those capable of providing assent (ClinicalTrials.gov Identifier: NCT01277510).

Study design

This was a multicenter phase 3 study consisting of a 30-week randomized, double-blind, placebo-controlled phase followed by a 30-week open-label phase. In both phases, patients received investigational product (i.e., cinacalcet or placebo in the double-blind phase and cinacalcet in the open-label phase) orally once daily at a starting dose of ≤ 0.20 mg/kg based on dry weight. The dose could be decreased or withheld at any time, or increased every 4 weeks at scheduled titration visits (weeks 4, 8, 12, 16, 20, and 24 of the double-blind phase and weeks 34, 38, 42, 46, 50, and 54 of the open-label phase) to a maximum dose of 180 mg or 4.2 mg/kg, whichever was lower, based on the patient’s observed plasma iPTH (target range, 100–300 pg/mL), corrected serum calcium levels, and patient safety information. Treatment compliance in this study was assessed on a monthly basis by pill count. Regardless of treatment assignment, all patients received standard-of-care treatment at the discretion of the investigator, which could include vitamin D sterols (calcitriol and its analogs), calcium supplements, and phosphate binders.

Patient eligibility was assessed during a 40-day screening period. Patients who met eligibility requirements for the study were randomized at a 1:1 ratio to placebo (control) or cinacalcet (active) for the double-blind phase; randomization was stratified by age group (6–< 12 and 12–< 18 years). The double-blind placebo-controlled phase of the study consisted of a 24-week period, during which the dose could be adjusted, followed by a 6-week efficacy assessment phase (EAP; Online Resource Fig. S1). Cinacalcet was prepared for oral administration as capsules (5 mg) for sprinkling, as film-coated tablets (30, 60, and 90 mg) for swallowing, and as a suspension (in a sucrose syrup) with matching placebos.

At week 30, patients who completed the double-blind EAP were eligible to enter the open-label phase, which consisted of a 24-week dose-adjustment period followed by a 6-week open-label maintenance period in which all patients received cinacalcet. There was no washout period between phases. Regardless of the final dose of investigational product in the double-blind period, the first dose of cinacalcet in the open-label phase was ≤ 0.20 mg/kg for all patients; the dose was then titrated as appropriate using the same dose adjustment algorithm as in the double-blind phase. Although the study was planned to be completed in 2015, the data monitoring committee stopped enrollment and placed the study on hold on January 31, 2013, because of a fatality.

Assessments

Blood samples were collected every 2 weeks and after dose adjustments to measure iPTH. Total serum calcium, phosphorus, and albumin concentrations were measured 1 week before each visit, at which time the dose of investigational product was allowed to be increased; blood collection was only required at weeks 5, 9, 13, 17, and 21 if the dose of investigational product was increased, decreased, or withheld at the previous visit. Visits to measure iPTH, corrected total serum calcium, phosphorus, and albumin were scheduled 5 to 7 days after any change in investigational product dose.

Plasma iPTH was measured using an immunometric assay (ADVIA Centaur iPTH Assay; Siemens Healthcare, Erlangen, Germany). Serum calcium was reported as a corrected value by the central laboratory based on calcium and albumin concentrations.

Endpoints

The primary endpoint in this study was the achievement of a ≥ 30% reduction from baseline in mean iPTH during the EAP. Secondary endpoints included achievement of a mean iPTH value ≤ 300 pg/mL during the EAP; percentage change in corrected total serum calcium, phosphorus, Ca × P, and ionized calcium from baseline to the respective mean values during the EAP; and growth velocity, calculated from height measurements, from baseline to week 30 and from week 30 to 60. Safety endpoints included nature, frequency, severity, and relationship to treatment of all adverse events (AEs); incidence of hypocalcemia; and changes in vital signs and laboratory parameters, including clinical chemistry and hematology.

Statistical analysis

The percentages of patients achieving iPTH reductions ≥ 30% from baseline during the EAP were estimated to be 60% and 15% for the cinacalcet and placebo groups, respectively. Using a two-sided Fisher exact test at an alpha level of 0.05, a planned sample size of 100 (50 per treatment group) would provide 99% power to detect the proposed difference, and 88% if the observed percentages were 45% and 15%, respectively.

Demographics, baseline characteristics, and exposure to investigational product were summarized by treatment group using descriptive statistics. The last-observation-carried-forward method was used in the analysis of the primary and secondary efficacy endpoints, except for the secondary efficacy endpoint of growth velocity, for which no imputation was done. Linear growth velocity was calculated as follows: 52 × change in height (cm)/number of weeks between assessments. The primary efficacy endpoint was analyzed using the Cochran-Mantel-Haenszel test stratified by baseline age group (6–< 12, 12–< 18 years) at a two-sided significance level of 0.05. The secondary endpoint of mean iPTH value ≤ 300 pg/mL was analyzed using the same method as for the primary endpoint, and the percentage change from baseline in mean corrected total serum calcium, phosphorus, and Ca × P was calculated by analysis of covariance (ANCOVA) using baseline age group as a covariate. The analyses of these secondary endpoints were adjusted for multiplicity using Holm’s procedure [15]. Growth velocity from baseline to week 30 and weeks 30 to 60, as well as percentage change from baseline in mean ionized calcium, was calculated by ANCOVA, with baseline age group as a covariate at a two-sided significance level of 0.05 without multiplicity adjustment.

Safety and data monitoring

Adverse events were coded according to the Medical Dictionary for Regulatory Activities, version 16.1, and graded according to the Common Terminology Criteria for Adverse Events, version 4.0 [16]. Potential symptoms of hypocalcemia that were monitored included numbness/tingling of fingers, toes, or area around the mouth; muscle aches; muscle cramps/spasms; stiffness of the arms, legs, or jaw; extreme drowsiness and inability to arouse; anxiety out of proportion with the situation; and heart rhythm problems. An independent data monitoring committee was formed to monitor the safety of the patients throughout the study by periodically reviewing all available safety data.

Results

Patients

This study was conducted in 26 study centers in nine countries. The first patient was enrolled June 28, 2011. Originally, the plan was to enroll approximately 100 patients; however, a fatality occurred after 43 patients had been enrolled. Regulatory authorities were notified, and the study was placed on clinical hold January 31, 2013, with suspension of investigational product. The study was subsequently terminated after a 14-month clinical hold; the primary completion date was April 30, 2014. For the 43 patients enrolled, the mean age for all patients was 13.2 years, 51% were female, and 72% were white. Of the 43 randomized patients, 22 received ≥ 1 dose of cinacalcet and 21 received ≥ 1 dose of placebo in the double-blind phase (Fig. 1). Twelve patients enrolled in the open-label phase, ten of whom received open-label cinacalcet: four who previously received cinacalcet and six who previously received placebo. Demographics and baseline characteristics were similar between groups, although slightly more patients were receiving hemodialysis in the cinacalcet group (Table 1). A total of 27 patients (62.8%) discontinued the study during the double-blind phase. Discontinuations were more frequent in the cinacalcet arm (77%) than in the placebo arm (48%). Most discontinuations during the double-blind phase were due to administrative decision (12 patients [27.9%]; 7 cinacalcet [31.8%], 5 placebo [23.8%]), followed by kidney transplant (8 patients [18.6%]; 6 cinacalcet [27.3%], 2 placebo [9.5%]), consent withdrawn (4 patients [9.3%]; 1 cinacalcet [4.5%], 3 placebo [14.3%]), noncompliance (1 patient [2.3%]; cinacalcet arm), and death (1 patient [2.3%]; cinacalcet arm). In the open-label phase, 8 (66.7%) discontinued: 6 (50.0%) for administrative decision and 2 (16.7%) for kidney transplant.
Fig. 1

Disposition of patients

Table 1

Patient demographics and baseline characteristics

Characteristic

Cinacalcet (n = 22)

Placebo (n = 21)

Total (N = 43)

Female, n (%)

12 (54.5)

10 (47.6)

22 (51.2)

Age, mean (SD), years

13.3 (3.6)

13.2 (2.9)

13.2 (3.3)

Age group, n (%), years

 6–< 12

6 (27.3)

5 (23.8)

11 (25.6)

 12–< 18

16 (72.7)

16 (76.2)

32 (74.4)

Race, n (%)

 White

16 (72.7)

15 (71.4)

31 (72.1)

 Black

5 (22.7)

6 (28.6)

11 (25.6)

 Other

1 (4.5)

0

1 (2.3)

Hispanic or Latino, n (%)

3 (13.6)

5 (23.8)

8 (18.6)

Dry weight, mean (SD), kg

45.3 (18.5)

46.1 (21.0)

45.7 (19.5)

Height, mean (SD), cm

148.7 (19.5)

146.0 (18.9)

147.4 (19.0)

Dialysis mode, n (%)

 Hemodialysis

15 (68.2)

12 (57.1)

27 (62.8)

 Peritoneal dialysis

7 (31.8)

9 (42.9)

16 (37.2)

Duration of dialysis, mean (SD), months

 Hemodialysis

21.3 (27.9)

16.3 (10.1)

19.3 (22.3)

 Peritoneal dialysis

21.0 (19.2)

31.5 (21.2)

26.6 (20.3)

Dialysate calcium, mean (SD), mEq/L

2.63 (0.48)

2.70 (0.38)

2.66 (0.43)

Baseline values, n (%)

 Vitamin D sterol usea

21 (95.5)

18 (85.7)

39 (90.7)

  Paricalcitol, IV

5 (22.7)

8 (38.1)

13 (30.2)

  Paricalcitol, oral

1 (4.5)

1 (4.8)

2 (4.7)

  Alfacalcidol, oral

8 (36.4)

5 (23.8)

13 (30.2)

  Calcitriol, IV

1 (4.5)

2 (9.5)

3 (7.0)

  Calcitriol, oral

6 (27.3)

2 (9.5)

8 (18.6)

 Nutritional vitamin D use

8 (36.4)

6 (28.6)

14 (32.6)

  Cholecalciferol

7 (31.8)

5 (23.8)

12 (27.9)

  Ergocalciferol

1 (4.5)

1 (4.8)

2 (4.7)

 Phosphate binder use

20 (90.9)

19 (90.5)

39 (90.7)

  Calcium-containing

14 (63.6)

13 (61.9)

27 (62.8)

  Sevelamer HCl

7 (31.8)

9 (42.9)

16 (37.2)

  Lanthanum carbonate

1 (4.5)

0

1 (2.3)

  Sevelamer carbonate

3 (13.6)

5 (23.8)

8 (18.6)

 Calcium supplement useb

5 (22.7)

2 (9.5)

7 (16.3)

 Growth hormone use

8 (36.4)

3 (14.3)

11 (25.6)

iPTH, mean (SD), pg/mL

757.1 (440.1)

795.8 (537.9)

776.0 (484.8)

Corrected total serum calcium, mean (SD), mg/dL

9.91 (0.54)

9.88 (0.62)

9.90 (0.58)

Serum phosphorus, mean (SD), mg/dL

6.68 (1.78)

6.37 (1.48)

6.53 (1.63)

Ca × P, mean (SD), mg2/dL2

65.99 (18.16)

62.95 (16.25)

64.50 (17.12)

Ca × P calcium phosphorus product, HCl hydrochloride, iPTH intact parathyroid hormone, IV intravenous

aIncludes IV or oral paricalcitol, doxercalciferol, alfacalcidol, and calcitriol

bIncludes calcium and calcium carbonate

In the cinacalcet group, 15 patients (68%) were receiving hemodialysis and seven (32%) were receiving peritoneal dialysis; in the placebo group, 12 (57%) were receiving hemodialysis and nine (43%) were receiving peritoneal dialysis. Mean baseline concentrations of iPTH, corrected calcium, phosphorus, and Ca × P were similar between treatment groups. Concomitant therapy use during the study was administered as expected and is shown in Table 2.
Table 2

Concomitant therapy

Concomitant therapy

Double-blind phase

Open-label phase

Cinacalcet (n = 22)

Placebo (n = 21)

Previously cinacalcet (n = 4)

Previously placebo (n = 6)

Vitamin D sterols, n (%)

22 (100)

19 (90.5)

4 (100)

6 (100)

 IV calcitriol

1 (4.5)

2 (9.5)

0

1 (16.7)

 Oral calcitriol

7 (31.8)

3 (14.8)

1 (25.0)

1 (16.7)

 IV paricalcitol

5 (22.7)

8 (38.1)

2 (50.0)

3 (50.0)

 Oral paricalcitol

4 (18.2)

1 (4.8)

2 (50.0)

0

 Oral alfacalcidol

8 (36.4)

5 (23.8)

1 (25.0)

1 (16.7)

Nutritional vitamin D, n (%)

9 (40.5)

10 (47.6)

1 (25.0)

3 (50.0)

 Cholecalciferol

7 (31.8)

6 (28.6)

1 (25.0)

0

 Ergocalficerol

2 (9.1)

4 (19.0)

0

3 (50.0)

Phosphate binders,a n (%)

21 (95.5)

20 (95.2)

4 (100)

6 (100)

 Calcium-containing

15 (68.2)

15 (71.4)

2 (50.0)

4 (66.7)

 Magnesium-containing

0

0

0

1 (16.7)

 Aluminum-containing

0

0

0

0

 Sevelamer HCl

9 (40.9)

9 (42.9)

3 (75.0)

0

 Lanthanum carbonate

2 (9.1)

0

0

1 (16.7)

 Sevelamer carbonate

3 (13.6)

6 (28.6)

0

4 (66.7)

 Other

0

0

0

0

Calcium supplements,b n (%)

7 (31.8)

6 (28.6)

2 (50.0)

2 (33.3)

 Calcium

1 (4.5)

2 (9.5)

1 (25.0)

0

 Calcium carbonate

6 (27.3)

3 (14.3)

1 (25.0)

2 (33.3)

 Calcium gluconate

0

1 (4.8)

0

0

 Calcium with vitamin D

1 (4.5)

0

1 (25.0)

0

HCl hydrochloride, IV intravenous

aPatients could use multiple types of phosphate binder; the subcategories are not mutually exclusive

bPatients could receive ≥ 1 type of calcium supplement and would be counted in multiple categories

Efficacy

Primary endpoint

Despite early termination of the study with a sample size that was smaller than planned, the study was still reasonably powered for the primary endpoint. A sample size of approximately 22 patients per treatment group would provide 82% power to detect the proposed difference with a two-sided Fisher exact test at an alpha level of 0.05. Before the clinical hold, 12 patients (54.5%) who received cinacalcet and four (19%) who received placebo achieved the primary endpoint of a ≥ 30% reduction in mean iPTH from baseline during the EAP (p = 0.017, stratified by age; Table 3). The difference between the cinacalcet and placebo groups in the proportion of patients who achieved the primary endpoint was 36% (95% CI, 9 to 62%).
Table 3

Percentage of patients achieving a ≥ 30% reduction in mean iPTH from baseline to the efficacy assessment phasea,b

Efficacy assessment phase

6–< 12 years

12–< 18 years

Total

Cinacalcet (n = 6)

Placebo (n = 5)

Cinacalcet (n = 16)

Placebo (n = 16)

Cinacalcet (n = 22)

Placebo (n = 21)

Patients achieving a ≥ 30% reduction in mean iPTH, n (%)

6 (100)

1 (20)

6 (37.5)

3 (18.8)

12 (54.5)

4 (19.0)

Test statistics

 Cochran-Mantel-Haenszel, chi-square

  

5.735 (p = 0.017)

 Odds ratio, cinacalcet/placebo

  

4.26 (95% CI, 0.99–18.30)

 Percentage difference, cinacalcet-placeboc

  

35.50 (95% CI, 8.76–62.24)

iPTH intact parathyroid hormone

aExcluding iPTH values collected after investigational product suspension

bFull analysis set: all randomized patients with ≥ 1 postbaseline assessment

cBased on the difference in proportions between treatment groups

Secondary endpoints

The percentages of patients achieving iPTH values ≤ 300 pg/mL during the EAP were 27% in the cinacalcet group and 24% in the placebo group. The difference between the cinacalcet and placebo groups in the proportion of patients who achieved this secondary endpoint was 3% (95% CI, − 23 to 30%). Other secondary endpoints assessed during the EAP of the double-blind phase are provided in Table 4; differences (95% CI) between the cinacalcet and placebo groups in the percentage changes in total serum calcium, serum phosphorus, and Ca × P were − 4% (− 9 to 1%), − 6.4% (− 21 to 8%), and − 10% (− 23 to 3%), respectively. The concentration and the percentage change in iPTH during the double-blind phase are shown in Fig. 2a–b. The concentration and the percentage change in corrected calcium, serum phosphorus, and Ca × P during the double-blind phase are shown in the Online Resource Fig. S2a–c and Fig. 3a–c. The calculated growth velocity (95% CI) from baseline to week 30 was 3.3 cm/year (0.8–5.8) in patients who received cinacalcet and 3.1 cm/year (0.7–5.6) in patients who received placebo. The sample size and duration of follow-up in the open-label phase were insufficient to provide meaningful results on growth velocity from week 30 to 60.
Table 4

Secondary endpointsa

Secondary endpoint

LS mean estimate

Difference in LS mean estimates, cinacalcet-placebo

95% CI

Cinacalcet

Placebo

Percentage change in corrected total serum calcium from baseline to mean value during the EAPb

− 4.6

− 1.0

− 3.7

− 8.6 to 1.3

Percentage change in serum phosphorus from baseline to mean value during the EAPb

2.9

9.3

− 6.4

− 21.0 to 8.2

Percentage change in Ca × P from baseline to mean value during the EAPb

− 2.0

8.0

− 10.0

− 22.5 to 2.6

Growth velocity calculated from baseline to end of double-blind phasec

3.3

3.1

0.2

− 3.1 to 3.6

Percentage change in ionized calcium from baseline to mean value during the EAPb

− 2.3

− 1.5

− 0.8

− 9.4 to 7.9

Ca × P calcium phosphorus product, EAP efficacy assessment phase, LS least squares

aFull analysis set: all randomized patients with ≥ 1 postrandomization assessment

bThe analyses included laboratory values collected before administration of investigational product was suspended

cThe end of the double-blind phase was at week 30 by design, but the last assessment in the double-blind phase was used because of the early termination of the study

Fig. 2

Median (IQR) intact parathyroid hormone (iPTH) concentration (a) and percentage change in iPTH (b) at scheduled visits in the double-blind phase by treatment group.a BL baseline of the double-blind phase, iPTH intact parathyroid hormone, IQR interquartile range. aSafety analysis set: all randomized patients who received ≥ 1 dose of the investigational product

Fig. 3

Percentage change in corrected total calcium (a), serum phosphorus (b), and Ca × P (c).a BL baseline of the double-blind phase, Ca × P calcium phosphorus product. aSafety analysis set: all randomized patients who received ≥ 1 dose of the investigational product

Exploratory endpoint

An exploratory endpoint of this study was the impact of cinacalcet on pubertal development (changes in the Tanner stage) at week 60; however, there were few patients with data available after the open-label phase due to the administrative decision for early termination, and thus, the analysis was limited. However, in brief, at baseline, 4 patients (18.2%) in the cinacalcet group and 4 patients (19.0%) in the placebo group were at the Tanner stage 1; 18 patients (81.8%) and 17 patients (81.0%) were at the Tanner stage ≥ 2, respectively. At the end of the double-blind phase, 37 patients had assessments: 5 patients (22.7%) in the cinacalcet group and 3 patients (14.3%) in the placebo group were at the Tanner stage 1; 13 patients (59.1%) and 16 patients (76.2%) were at the Tanner stage ≥ 2, respectively. At the end of the open-label phase, 11 patients had assessments available: 1 patient (8.3%) was at the Tanner stage 1 and 10 patients (90.9%) were at the Tanner stage ≥ 2.

Exposure

In the double-blind phase, the mean duration of exposure to the investigational product was similar between the cinacalcet and placebo groups (110 versus 123 days, respectively). For doses actually taken, when examined across the totality of the double-blind phase, the mean initial weight-adjusted dose for cinacalcet was 0.18 mg/kg/day, which increased to a mean maximum weight-adjusted dose of 0.99 mg/kg/day. For doses actually taken, when restricted to the EAP, the mean average weight-adjusted dose for cinacalcet was 1.54 mg/kg/day, corresponding to a mean average daily dose of 50.4 mg/day. Additional details on patient exposure to either cinacalcet or placebo, including prescribed doses, are shown in the Online Resource Table S1.

In the open-label phase, the mean duration of cinacalcet exposure was 119 days, ranging between 50 and 210 days for those patients who initially received cinacalcet and 12–203 days for those who initially received placebo. Overall, in the open-label phase, the mean average prescribed weight-adjusted cinacalcet dose during the maintenance phase was 0.66 mg/kg/day, with a mean weight-adjusted average actual daily cinacalcet dose of 0.77 mg/kg/day and an average daily dose of 34.6 mg/day. The highest daily cinacalcet dose in the open-label phase was 60 mg and was prescribed to four patients (40%); the mean (range) maximum prescribed weight-adjusted daily dose of cinacalcet was 0.70 (0.2–1.9) mg/kg/day.

Safety

In the double-blind phase, 82% of patients in the cinacalcet group and 86% of patients in the placebo group had at least one treatment-emergent AE (TEAE; Table 5). The most common AEs in the cinacalcet and placebo groups were vomiting (32%, 24%, respectively), hypocalcemia (23%, 19%), nausea (18%, 14%), and hypertension (14%, 24%). Seven patients (32%) in the cinacalcet group and 10 (48%) in the placebo group had grade ≥ 3 TEAEs; nine patients in each group (41% and 43%, respectively) experienced serious AEs. The most common serious AE was hypertension (9%; n = 2) in the cinacalcet group and diarrhea, pyrexia, and dehydration (10% each; n = 2 each) in the placebo group. Seven patients (32%) in the cinacalcet group and three (14%) in the placebo group had a corrected total serum calcium concentration < 8.4 mg/dL (mild hypocalcemia) at any time during the double-blind phase. Five patients (23%) in the cinacalcet group and one (5%) in the placebo group had a corrected total serum calcium concentration < 8.0 mg/dL (moderate hypocalcemia) and three patients (14%) in the cinacalcet group and no patients in the placebo group had a corrected total serum calcium concentration < 7.5 mg/dL (severe hypocalcemia). Data linking low calcium concentrations with symptoms of hypocalcemia were not available. Potential symptoms of hypocalcemia included muscle spasms (14%, 5%), myalgia (14%, 5%), and tremor (14%, 0); AEs of interest that were identified risks were hypocalcemia (23%, 19%), convulsions/seizures (0, 10%), hypotension (9%, 5%), cardiac failure (5%, 0), and hypersensitivity (9%, 14%).
Table 5

AEs in the double-blind phasea

AE, n (%)

Cinacalcet (n = 22)

Placebo (n = 21)

All treatment-emergent AEs

18 (81.8)

18 (85.7)

 Grade ≥ 2

13 (59.1)

16 (76.2)

 Grade ≥ 3

7 (31.8)

10 (47.6)

 Grade ≥ 4

1 (4.5)

2 (9.5)

 Serious AEs

9 (40.9)

9 (42.9)

 AEs leading to withdrawal of investigational product

0

2 (9.5)

 Fatal AEs

1 (4.5)

0

Treatment-emergent AEs in ≥ 5% of patients in either treatment armb

 Vomiting

7 (31.8)

5 (23.8)

 Hypocalcemia

5 (22.7)

4 (19.0)

 Nausea

4 (18.2)

3 (14.3)

 Abdominal pain

3 (13.6)

3 (14.3)

 Headache

3 (13.6)

2 (9.5)

 Hypertension

3 (13.6)

5 (23.8)

 Influenza

3 (13.6)

1 (4.8)

 Muscle spasms

3 (13.6)

1 (4.8)

 Myalgia

3 (13.6)

1 (4.8)

 Tremor

3 (13.6)

0

 Anxiety

2 (9.1)

0

 Catheter site infection

2 (9.1)

0

 Device-related infection

2 (9.1)

2 (9.5)

 Diarrhea

2 (9.1)

4 (19.0)

 Dizziness

2 (9.1)

0

 Hypotension

2 (9.1)

1 (4.8)

 Musculoskeletal stiffness

2 (9.1)

0

 Nasopharyngitis

2 (9.1)

1 (4.8)

 Chills

1 (4.5)

2 (9.5)

 Constipation

1 (4.5)

3 (14.3)

 Cough

1 (4.5)

3 (14.3)

 Hyperkalemia

1 (4.5)

3 (14.3)

 Pyrexia

1 (4.5)

4 (19.0)

 Upper respiratory tract infection

0

4 (19.0)

 Arteriovenous fistula site complication

0

3 (14.3)

 Nasal congestion

0

3 (14.3)

 Back pain

0

2 (9.5)

 Dehydration

0

2 (9.5)

 Local swelling

0

2 (9.5)

 Oropharyngeal pain

0

2 (9.5)

 Pain

0

2 (9.5)

 Vitamin D deficiency

0

2 (9.5)

AE adverse event

aSafety analysis set: all randomized patients who received ≥ 1 dose of the investigational product

bPreferred term; coded using Medical Dictionary for Regulatory Activities, version 16.1

A fatal AE occurred during the double-blind period in a female adolescent with a prolonged QT interval at baseline receiving peritoneal dialysis, cinacalcet (90 mg at the time of death), and multiple concomitant medications. During study week 23, she acutely developed severe nausea, vomiting, diarrhea, dehydration, and fever (102.4 °F) and was treated with acetaminophen and ondansetron. Later the same day, she went into fatal cardiopulmonary arrest. On the day of death, she had a PTH level of 439 pg/dL, and a laboratory report that became available after the fatality showed a total calcium of 4.5 mg/dL and a corrected calcium of 5.3 mg/dL on the morning of the patient’s death. Although the fatality was determined to be multifactorial, a causal role for hypocalcemia as a result of treatment with cinacalcet could not be excluded.

In the open-label phase, TEAEs were reported for nine of ten patients who received ≥ 1 dose of investigational product (90%; Online Resource Table S2). During the open-label phase, four patients (40%) experienced serious AEs (esophageal varices, peritonitis, pneumonia, urinary tract infection, increased hemoglobin, hypocalcemia, hypersensitive encephalopathy, and hypertension; n = 1 each). AEs reported in more than one patient were hypocalcemia (40%, n = 4), nausea (30%, n = 3), headache, hypertension, paresthesia, abdominal pain, and pyrexia (20%, n = 2 each). AEs of interest that were identified as treatment risks were hypocalcemia (40%, n = 4), hypotension (10%, n = 1), and hypersensitivity (10%, n = 1). Overall, no clinically significant changes were observed in vital signs, hematology parameters, or clinical chemistry parameters, with the exception of median iPTH and corrected total calcium concentrations (Fig. 3).

Discussion

In this multicenter study of pediatric patients with SHPT, the proportion of patients achieving a ≥ 30% reduction from baseline in mean iPTH during the EAP was significantly higher in the cinacalcet group compared with the placebo group. Furthermore, although not statistically significant, a numerically larger proportion of patients in the cinacalcet group achieved mean iPTH values ≤ 300 pg/mL during the EAP, and the least squares mean in the percentage change in corrected calcium, phosphorus, and Ca × P was numerically reduced further with cinacalcet than with placebo. The incidence of AEs was comparable between groups, and the safety profile in this pediatric study was generally consistent with the known safety profile of cinacalcet in adults with SHPT receiving dialysis [7]. Hypocalcemia, an AE of interest, was reported in similar proportions of pediatric patients in the cinacalcet and placebo groups in the double-blind phase of the study.

Efficacy results from the present pediatric study are also consistent with a single-center prospective study of cinacalcet in pediatric patients [11] and with studies evaluating cinacalcet in adults with SHPT receiving dialysis [17, 18, 19]. In the single-center pediatric study, all patients (n = 28) experienced a ≥ 60% reduction in serum iPTH [11]. Similarly, in the earlier studies of adult patients, 38% to 64% of patients treated with cinacalcet had a ≥ 30% reduction from baseline in PTH levels versus 8% to 23% of patients treated with placebo, which is comparable with the results observed in the present study [17, 18, 19].

The incidences of AEs observed in this study were similar between patients receiving cinacalcet and placebo. Safety results in this pediatric study were also consistent with those observed in other studies of cinacalcet in pediatric patients [12, 20] and in adult patients [17, 18, 19]. The most common AEs reported with cinacalcet treatment in this study were vomiting, hypocalcemia, and nausea, consistent with previous studies [17, 18, 19]. In turn, careful monitoring of serum calcium levels is recommended, and concomitant therapy (e.g., calcium supplements, calcium-based phosphate binders, vitamin D sterols) should be provided if needed.

While not approved in the USA for pediatric use, cinacalcet is approved for pediatric use in the EU, and product labeling notes that caution is advised in patients with other risk factors for QT prolongation such as patients with known congenital long QT syndrome or in patients receiving medicinal products known to cause QT prolongation. Labeling also suggests that once the maintenance dose has been established, serum calcium should be measured weekly.

Treatment compliance in this study was assessed on a monthly basis by pill count. However, the counts at the end of the month did not necessarily reflect whether a patient took the correct dose each day. However, only one patient (cinacalcet group) discontinued the trial because of noncompliance, so it is unlikely that noncompliance is a notable concern in the analysis of these data.

Although the US Food and Drug Administration has approved cinacalcet for use in adult patients only [7], based on the results of this study, the European Medicines Agency recently broadened the approved indications for cinacalcet to include use in children 3 years or older receiving maintenance dialysis for whom SHPT has not been adequately controlled with standard-of-care therapy [21].

This study had several limitations. Premature discontinuation of the study limited the exposure period for cinacalcet and the duration of follow-up for this study; thus, growth velocity during the open-label extension could not be evaluated. Given the importance of preserving a positive calcium and phosphate balance in the growing patient, serum calcium should be maintained at the high end of the recommended range based on patient age. Moreover, the incidence of study discontinuation was higher in the cinacalcet arm than in the placebo arm, although this difference was largely due to the random occurrence of kidney transplants (cinacalcet arm, 27%; placebo arm, 10%). Lastly, there was substantial intra- and interpatient variability that was inherent to the iPTH assay used in this study [22].

Although fewer data were collected than originally planned because of the multifactorial fatality that led to early termination, this is the only large, double-blind, placebo-controlled study of cinacalcet in children with SHPT and, most importantly, adds valuable information to that previously collected in a prospective single-arm study [11] and retrospective single-center studies [12, 13, 14].

In conclusion, despite early study termination, the treatment effect observed with cinacalcet in reducing plasma PTH in pediatric patients 6 to 18 years of age with SHPT receiving dialysis is consistent with what has been observed in adults. Similarly, the observed safety profile of cinacalcet was also generally consistent with that observed in other pediatric studies and the known safety profile of cinacalcet in the treatment of adults with SHPT as listed in the prescribing information [7]. These data suggest that cinacalcet may meet an unmet medical need for the pediatric dialysis population. Due to the premature discontinuation of the trial, uncertainties remain regarding the long-term effects of cinacalcet on growth and development in the pediatric population, and close supervision and monitoring for hypocalcemia and its secondary effects is warranted.

Notes

Acknowledgments

The authors acknowledge Meghan Johnson, PhD, and James Balwit, MS, CMPP (Complete Healthcare Communications, LLC, a CHC Group company, North Wales, PA), whose work was funded by Amgen Inc., as well as Holly Tomlin, MPH, CMPP (Amgen Inc. at time of writing, currently Tomlin Health Sciences Communications), and William W. Stark, Jr., PhD (Amgen employee and stockholder), for the assistance in writing this manuscript.

Funding

This study was funded by Amgen Inc.

Compliance with ethical standards

Conflicts of interest

BAW and SS have served as consultants for Amgen Inc. JNI was an employee and stockholder of Amgen Inc. at the time the work was done. BD was an employee of Amgen Europe GmbH at the time the work was done. GH has received grant funding from Amgen Inc. XJ is an employee and stockholder of Amgen Inc. BL was the principal investigator for a clinical study site for the study described in this manuscript. JVW is a member of the Ferring Safety Board, Astellas Safety and Investigator Board for Solifenacin, Mitsubishi Safety Board, and Alexion Registry Review Board and receives research funding and is on the speakers bureau for Alexion Pharmaceuticals, Inc. FS has received personal fees from Amgen Inc. GA declares no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

The study protocol was approved by the institutional review board or independent ethics committee of each study center.

Informed consent

Informed consent or assent, when applicable, because the youngest participants cannot consent, was obtained from all individual participants included in the study and/or their parent or legally acceptable representative.

Data sharing

There is a plan to share data. This may include de-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request, also related data dictionaries, study protocol, statistical analysis plan, informed consent form, and/or clinical study report. Data sharing requests relating to data in this manuscript will be considered after the publication date and (1) this product and indication (or other new use) have been granted marketing authorization in both the USA and Europe, or (2) clinical development discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for these data. Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labeling. A committee of internal advisors reviews requests. If not approved, requests may be further arbitrated by a Data Sharing Independent Review Panel. Requests that pose a potential conflict of interest or an actual or potential competitive risk may be declined at Amgen’s sole discretion and without further arbitration. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the following: http://www.amgen.com/datasharing.

Supplementary material

467_2018_4116_MOESM1_ESM.pdf (202 kb)
ESM 1 (PDF 201 kb)

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Copyright information

© IPNA 2018

Authors and Affiliations

  • Bradley A. Warady
    • 1
    Email author
  • Janet N. Iles
    • 2
  • Gema Ariceta
    • 3
  • Bastian Dehmel
    • 4
  • Guillermo Hidalgo
    • 5
  • Xun Jiang
    • 2
  • Benjamin Laskin
    • 6
  • Shahnaz Shahinfar
    • 6
    • 7
  • Johan Vande Walle
    • 8
  • Franz Schaefer
    • 9
  1. 1.Division of Pediatric NephrologyChildren’s Mercy Kansas CityKansas CityUSA
  2. 2.Amgen Inc.Thousand OaksUSA
  3. 3.University Hospital Vall d’ HebronBarcelonaSpain
  4. 4.Amgen Europe GmbHZugSwitzerland
  5. 5.Brody School of MedicineEast Carolina UniversityGreenvilleUSA
  6. 6.Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  7. 7.S. Shahinfar Consulting Inc.Newtown SquareUSA
  8. 8.Ghent UniversityGhentBelgium
  9. 9.Heidelberg University HospitalHeidelbergGermany

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