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Hyperparathyroidism, Secondary

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Vascular Calcification

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Female Urogenital Diseases and Pregnancy Complications

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Bone Density Conservation Agents

Cinacalcet

Hormones

Calcium

Calcium, Dietary

Hormone Antagonists

Oral Cinacalcet treatment arm, 25mg daily to be administered and gradually step up as required to control iPTH between 2 - 9 times lab reference range, Maximum dose to be given is 100mg daily

Surgical total parathyroidectomy with forearm autografting will be performed for patients randomized to this arm.

oral cinacalcet 25mg once daily as a start and up titrated by 25mg daily according to response in lowering PTH and maximum oral dose allowed is 100mg daily

Surgical total parathyroidectomy with forearm autografting will be performed

Surgical total parathyroidectomy with forearm autografting

Angela YM Wang, MD, PhD

This is a pilot, prospective randomized controlled study with the primary objective to evaluate and compare medical treatment of severe SHPT, namely oral cinacalcet versus surgical treatment, that is, parathyroidectomy with forearm autografting, on the progression of coronary artery and valvular calcification and left ventricular mass index in endstage renal disease patients receiving peritoneal dialysis over 12 months. The change in arterial stiffening, left ventricular volume, aortic valve calcium score and bone mineral density, nutritional status and biochemical parameters, quality of life measures will be evaluated as secondary objectives of this study.

Patients with severe secondary hyperparathyroidism (SHPT) are frequently complicated with vascular calcification. There is some suggestion that subtotal parathyroidectomy may reduce or stabilize vascular calcium scores in dialysis patients. Experimental data suggests that SHPT plays an important role in mediating uraemic arterial disease and that parathyroidectomy largely prevented the development of calcification. Cinacalcet has emerged as a novel therapy for the treatment of SHPT and has been shown to reduce the need for surgical parathyroidectomy. However, their effects on vascular, cardiac, bone and nutrition status have not been evaluated and compared with parathyroidectomy.

Cinacalcet medical treatment versus total parathyroidectomy with forearm autografting surgical treatment

Cinacalcet Versus Parathyroidectomy in Peritoneal Dialysis Patients

Comparison of Medical Therapy (Oral Cinacalcet) Versus Surgical Therapy (Total Parathyroidectomy) on Vascular/Valvular Calcification in Chronic Peritoneal Dialysis Patients With Secondary Hyperparathyroidism - A Pilot Randomized Study

change in left ventricular volume and ejection fraction

Change in aortic valve and mitral valve calcium score

change in augmentation index and heart rate adjusted augmentation index

change in bone mineral density at forearm, spine and femur

Kidney Disease Outcome Quality Initiatives (KDOQI QOL domain scores)

Change in biochemical parameter Serum calcium and phosphorus

Change in biochemical parameter Parathyroid hormone

Change in biochemical parameter alkaline phosphatase

CHange in biochemical parameter serum albumin

change in systolic and diastolic blood pressure

The University of Hong Kong

Honorary Associate Professor

Renal Insufficiency, Chronic

Chronic Disease

Disease Attributes

Micronutrients

Vitamins

Other Dietary Supplements

Vitamin D

Cholecalciferol

Parathyroid Hormone

Vitamin D3

Calciferol

Phytosterol

Prior to the partial clinical hold, the starting dose was 0.25 mg/kg (based on dry weight) and was titrated upwards (maximum allowed daily dose of 4.2 mg/kg) based on plasma intact parathyroid hormone (iPTH), corrected serum calcium levels obtained monthly, and adverse signs and symptoms.

After the partial clinical hold the starting dose was 0.20 mg/kg (based on dry weight) and was titrated upwards (maximum allowed daily dose of 2.5 or 60 mg, whichever was lower) based on plasma iPTH, corrected serum calcium levels obtained monthly, weekly monitoring of ionized calcium levels, and adverse signs and symptoms.

All participants also received standard of care, which may have included vitamin D sterols.

Cinacalcet was provided as 5 mg capsules that were opened, and the contents were either sprinkled on soft food or suspended into a sucrose syrup to create a liquid suspension for administration. All doses were administered with food or shortly after a meal at the same time daily.

Cinacalcet hydrochloride

Standard of care may have included vitamin D sterols (25 OH vitamin D and/or 1-25 OH vitamin D and its analogs) at the discretion of the investigator.

Standard of Care

The primary objective was to characterize corrected serum calcium levels on treatment with cinacalcet in pediatric patients with secondary hyperparathyroidism (HPT).

This is a multicenter, 26-week, single-arm, open-label, safety study. Participants were to remain on study for 26 weeks or until time of kidney transplantation, whichever came first.

The study and enrollment was placed on partial clinical hold in February 2013 which resulted in changes to the protocol. The study was restarted in April 2014 following these changes.

Participants who completed the 26-week study or were on study when the study was closed in June 2016 were eligible to participate in an open-label extension study (Study 20140159; NCT02341417).

Safety & Tolerability of Cinacalcet in Pediatric Patients With Chronic Kidney Disease and Secondary Hyperparathyroidism

An Open-label, Single-arm Study to Assess the Safety & Tolerability of Cinacalcet in Addition to Standard of Care in Pediatric Subjects Age 28 Days to < 6 Yrs With Chronic Kidney Disease & Secondary Hyperparathyroidism Receiving Dialysis

Hypocalcemia was defined as corrected serum calcium levels \< 9.0 mg/dL (2.25 mmol/L) for participants aged 28 days to \< 2 years, and \< 8.4 mg/dL (2.1 mmol/L) for participants aged ≥ 2 years to \< 6 years at any time during the study.

A participant was considered to have achieved \> 30% reduction in iPTH from baseline at any 2 consecutive measurements if percent change of any two consecutive post-baseline iPTH values were \< -30% regardless if there was a missing value in between.

A participant was considered to have achieved ≥ 30% reduction in iPTH if the percent change of any post-baseline iPTH value was ≤ -30% from baseline.

A participant was considered to have achieved iPTH between 200 and 300 pg/mL (21.2 and 31.8 pmol/L) at any 2 consecutive measurements if any two consecutive post-baseline iPTH values were within the range regardless if there was a missing value in between. The analysis included all enrolled subjects with at least 1 post-baseline assessment.

A participant was considered to have achieved iPTH \< 300 pg/mL (31.8 pmol/L) during the study if any post-baseline iPTH value was \< 300 pg/mL.

Amgen

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Cohort 1 consists of participants enrolled before the partial clinical hold. Participants received cinacalcet administered daily for 24 weeks. The starting dose was 0.25 mg/kg (based on dry weight) with dose adjustments and withholding based on plasma intact parathyroid hormone (iPTH), corrected serum calcium levels obtained monthly, and adverse signs and symptoms; the maximum allowed daily dose was 4.2 mg/kg.

Cohort 1

Cohort 2 consists of participants enrolled after the partial clinical hold. Participants received cinacalcet administered daily for 24 weeks. The starting dose was 0.20 mg/kg (based on dry weight) with dose adjustments and withholding based on plasma iPTH, corrected serum calcium levels obtained monthly, weekly monitoring of ionized calcium levels, and adverse signs and symptoms; the maximum allowed daily dose was 2.5 mg/kg/day or 60 mg, whichever was lower.

Cohort 2

Participants received cinacalcet administered daily for 24 weeks.

Total

Age, Continuous

28 days to < 2 years

2 years to < 6 years

Age, Customized

Sex: Female, Male

American Indian or Alaska Native

Asian

Black or African American

Native Hawaiian or Other Pacific Islander

White

Other

Race/Ethnicity, Customized

Hispanic or Latino

Not Hispanic or Latino

Corrected Serum Calcium

Intact Parathyroid Hormone

Study Director

The analysis included participants who received at least 1 dose of cinacalcet and had at least 1 measured serum calcium value while on cinacalcet (calcium analysis set).

Percentage of Participants With Hypocalcemia

Percentage of Participants With Corrected Serum Calcium Levels < 8.8 mg/dL (2.2 mmol/L) During the Study

Week 3 (n = 7, 9, 16)

Week 7 (n = 4, 9, 13)

Week 11 (n = 4, 8, 12)

Week 15 (n = 2, 7, 9)

Week 19 (n = 1, 3, 4)

Week 22 (n = 0, 1, 1)

Week 24 (n = 0, 1, 1)

The analysis included all enrolled participants with at least 1 post-baseline assessment (full analysis set) and with available data at each time point.

Percent Change From Baseline in Intact Parathyroid Hormone (iPTH)

Week 3 (n = 7, 10, 17)

Week 7 (n = 4, 8, 12)

Percent Change From Baseline in Corrected Serum Calcium

Week 19 (n = 1, 2, 3)

Percent Change From Baseline in Serum Phosphorous

Percent Change From Baseline in Calcium Phosphorus Product (Ca x P)

The analysis included all enrolled participants with at least 1 post-baseline assessment (full analysis set).

Percentage of Participants Who Achieved > 30% Reduction in iPTH From Baseline at Any Two Consecutive Measurements

Percentage of Participants Who Achieved ≥ 30% Reduction in iPTH From Baseline During the Study

Percentage of Participants Who Achieved iPTH Values Between 200 and 300 pg/mL at Any Two Consecutive Measurements

The analysis included all enrolled subjects with at least 1 post-baseline assessment (full analysis set).

Percentage of Participants Who Achieved iPTH Values < 300 pg/mL During the Study

The Pharmacokinetic/ Pharmacodynamic (PK/PD) analysis set includes all participants who received at least one dose of study drug and had at least one evaluable PK parameter.

Dose- and Weight-Normalized Maximum Plasma Concentration (Cmax) of Cinacalcet

Dose- and Weight-Normalized Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Cinacalcet

Overall Study

stepwise dose of cinacalcet + regular medical medication including vit D

conventional treatment for secondary HPT including vit D and phosphate binder

cinacalcet

control

This study is designed in order to investigate the effect of cinacalcet in combination with routine conventional medical management for treatment of secondary hyperparathyroidism (SHPT) and Ca, P control. This study will compare the efficacy of a cinacalcet-based regimen with unrestricted conventional care (vitamin D and phosphate binders) for achieving the stringent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) targets for dialysis patients.

Cinacalcet stUdy for Peritoneal Dialysis Patients In Double Arm on the Lowing Effect OF iPTH Level

Phase 4 Study of Cinacalcet Efficacy in Combination With Vitamin D for the Treatment of Secondary Hyperparathyroidism in Peritoneal Dialysis Patients

Abdominal aortic calcification score (AAC, 0-24) will be measured at baseline and at 20 weeks according to Kauppila et al (Atherosclerosis 2004)

Serum alkaline phosphatase measured at baseline and 20 weeks

Elevated serum levels of fibroblast growth factor-23 (FGF23) is associated with adverse outcomes in dialyzed patients. Therefore, we added analysis of change in FGF23 levels between two treatments to explore the cinacalcet effect in lowering FGF23.

Jeil-Kirin Pharmaceutical Inc.

Seoul National University Hospital

Associate Professor

Vasoconstrictor Agents

Calcitriol

Participants received standard of care and placebo once daily for 30 weeks during the double-blind phase. During the open-label phase, participants received cinacalcet with standard of care for an additional 30 weeks. The starting dose of cinacalcet was ≤ 0.20 mg/kg based on dry weight, and could be titrated up according to plasma iPTH and serum calcium levels every 4 weeks up to Week 54 to a maximum dose of 4.2 mg/kg.

Participants received standard of care and cinacalcet once daily for 30 weeks during the double-blind phase. The starting dose of cinacalcet was ≤ 0.20 mg/kg based on dry weight, and could be titrated up according to plasma iPTH and serum calcium levels every 4 weeks until Week 24 to a maximum dose of 4.2 mg/kg. During the open-label phase participants continued to receive cinacalcet with standard of care for an additional 30 weeks.

Cinacalcet was prepared for oral administration as both capsules for sprinkling and film coated tablets for swallowing.

cinacalcet capsule

Placebo tablets and capsules for sprinkling identical to active treatment.

placebo

All participants, regardless of treatment assignment, will receive standard of care with vitamin D sterols (calcitriol and its analogs), as prescribed by the treating physician.

The purpose of this study is to assess the safety and efficacy of adding cinacalcet to the current treatment of secondary hyperparathyroidism in children currently receiving dialysis compared to a treatment regimen that does not include cinacalcet.

Secondary hyperparathyroidism (SHPT) is a condition that can develop early in patients with chronic kidney disease (CKD), usually gets worse over time, and is known to cause problems for patients on dialysis. Children on dialysis can have a wide range of bone and growth issues, and common treatments have a chance of making these things worse by increasing serum calcium and serum phosphorus. Cinacalcet has been shown to be effective in controlling parathyroid hormone (PTH), calcium and phosphorus in adults. The purpose of this study is to show that including cinacalcet in the treatment of SHPT will lower the levels of intact parathyroid hormone (iPTH) in a larger number of pediatric patients with CKD who are receiving dialysis, compared to a treatment regimen that does not include cinacalcet.

Pediatric Chronic Kidney Disease Safety and Efficacy

A Randomized, Double-blind, Placebo Controlled Study to Assess the Efficacy and Safety of Cinacalcet HCl in Pediatric Subjects With Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Dialysis

The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase (EAP; Weeks 25 - 30). When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available post-baseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.

The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used.

Serum calcium was reported as a corrected value by the central laboratory based on calcium and albumin concentrations: Corrected total calcium (mg/dL) = measured total serum calcium (mg/dL) + 0.8 (4.0 - Serum albumin (g/dL)). The efficacy assessment value is based on the scheduled assessment(s) taken during the efficacy assessment phase. When multiple assessments were available, the average of those was used. If an efficacy measurement during the EAP was missing, the mean of the last 2 available postbaseline values in the dose-titration phase was used. If only one post-baseline value was available, this single value was used."

Linear growth velocity (cm/year) = 52 x change in height (cm) / number of weeks between the two assessments. End of double-blind phase visit was at Week 30 by design but the last assessment in the double-blind phase was used due to the early termination of the study.

Linear growth velocity (cm/year) = 52 x change in height (cm) / number of weeks between the two assessments. End of open-label phase visit was at Week 60 by design but the last assessment in the open-label phase was used due to the early termination of the study.

Double-blind Phase: Placebo

Double-blind Phase: Cinacalcet

Open-label Phase: Previous Placebo

Open-label Phase: Previous Cinacalcet

Placebo

Participants received standard of care and cinacalcet once daily for 30 weeks during the double-blind phase. The starting dose of cinacalcet was ≤ 0.20 mg/kg based on dry weight, and could be titrated up according to plasma iPTH and serum calcium levels every 4 weeks until Week 24 to a maximum dose of 4.2 mg/kg. During the open-label phase participants continued to receive cinacalcet with standard of care for an additional 30 weeks. Regardless of the titration level reached at the last dose of IP in the double-blind phase, all participants started titration at ≤ 0.20 mg/kg based on dry weight.

6 to < 12 years

12 to < 18 years

Intact Parathyroid Hormone (iPTH)

Serum calcium was reported as a corrected value by the central laboratory based on calcium and albumin concentrations:

Corrected total calcium (mg/dL) = measured total serum calcium (mg/dL) + 0.8 (4.0 - Serum albumin (g/dL)).

Corrected Total Serum Calcium

Serum Phosphorous

The study was terminated early with a smaller sample size. However, the study was still sufficiently powered for the double-blind phase. The data collected in the open-label phase is very sparse.

A hierarchical testing procedure was used to test the primary and biochemical secondary endpoints (Outcome Measures 1-5). The primary endpoint was tested at a significance level of 0.05. The four biochemical secondary endpoints were to be tested using Holm's method at 0.05 should the primary endpoint achieve a significant result.

Full analysis set, which includes all randomized participants with at least 1 post-baseline assessment.

Percentage of Participants Achieving ≥ 30% Reduction in Mean iPTH From Baseline to the Efficacy Assessment Phase

The secondary endpoint with the smallest p-value was first compared at a significance level of 0.0125. If the p-value was \> 0.0125, all 4 secondary endpoints were non-significant; if ≤ 0.0125, the null hypothesis for that endpoint was rejected. Next, the 2nd smallest p-value was compared at a level of 0.0167; if \> 0.0167, the remaining 3 endpoints were not significant, or, the null hypothesis of that endpoint was rejected. The other 2 endpoints were analyzed similarly, at 0.025 and 0.05.

Percentage of Participants Achieving Mean iPTH ≤ 300 pg/mL (31.8 Pmol/L) During the Efficacy Assessment Phase

Percent Change From Baseline in Mean Corrected Total Serum Calcium During the Efficacy Assessment Period

Full analysis set; data for one participant in the Placebo group were not available.

Percent Change From Baseline in Mean Serum Phosphorus During the Efficacy Assessment Phase

Percent Change From Baseline in Mean Phosphorous Product (Ca x P) During the Efficacy Assessment Phase

Full analysis set; the last assessment in the double-blind phase was used due to the early termination of the study. Only participants with available data are included in the analysis.

Growth Velocity From Baseline to End of Double-blind Phase

Full analysis set. Only participants with available data were included in the anaysis.

Growth Velocity From End of Double-blind Phase to End of Open-label Phase

Full analysis set; only participants with available data were included in the analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cinacalcet Versus Parathyroidectomy in Peritoneal Dialysis Patients	NCT01447368	Kidney Failure Secondary Hyper... Vascular Diseas...	Cinacalcet Surgical total ...	18 Years - 75 Years	The University of Hong Kong
Safety & Tolerability of Cinacalcet in Pediatric Patients With Chronic Kidney Disease and Secondary Hyperparathyroidism	NCT01439867	Chronic Kidney ... Hyperparathyroi...	Cinacalcet hydr... Standard of Car...	28 Days - 2189 Days	Amgen
Safety & Tolerability of Cinacalcet in Pediatric Patients With Chronic Kidney Disease and Secondary Hyperparathyroidism	NCT01439867	Chronic Kidney ... Hyperparathyroi...	Cinacalcet hydr... Standard of Car...	28 Days - 2189 Days	Amgen
Cinacalcet Versus Parathyroidectomy in Peritoneal Dialysis Patients	NCT01447368	Kidney Failure Secondary Hyper... Vascular Diseas...	Cinacalcet Surgical total ...	18 Years - 75 Years	The University of Hong Kong
Cinacalcet stUdy for Peritoneal Dialysis Patients In Double Arm on the Lowing Effect OF iPTH Level	NCT01101113	Secondary Hyper...	cinacalcet control	18 Years - 70 Years	Seoul National University Hospital
Pediatric Chronic Kidney Disease Safety and Efficacy	NCT01277510	Chronic Kidney ... Hyperparathyroi... Hyperparathyroi... Kidney Disease Secondary Hyper...	cinacalcet caps... placebo Standard of Car...	6 Years - 17 Years	Amgen
Cinacalcet stUdy for Peritoneal Dialysis Patients In Double Arm on the Lowing Effect OF iPTH Level	NCT01101113	Secondary Hyper...	cinacalcet control	18 Years - 70 Years	Seoul National University Hospital

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