Chronic Kidney Disease, Hyperparathyroidism, Secondary, Secondary Hyperparathyroidism
Conditions
Keywords
pediatric, CKD, dialysis, paediatric
Brief summary
The primary objective of the study was to evaluate the safety and tolerability of cinacalcet after a single oral dose in children aged 28 days to less than 6 years with chronic kidney disease receiving dialysis.
Interventions
DRUGCinacalcet
Single, oral dose of 0.25 mg/kg cinacalcet
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 2190 Days
Healthy volunteers
No
Inclusion criteria
* Subject's parent, or legally acceptable guardian, must sign an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) approved Informed Consent Form. * Subjects 28 days to \< 6 years of age with chronic kidney disease (CKD) and secondary hyperparathyroidism (sHPT) as diagnosed by principal investigators, undergoing hemodialysis or peritoneal dialysis at the time of screening (subjects 6 months or older should have been receiving dialysis for ≥ 1 months) and who have not received any cinacalcet HCl therapy for at least 2 weeks prior to dosing on Day 1 * Free of any disease or condition (other than those diseases or conditions related to their renal disease that, in the opinion of the investigator, would impact the subject's safety or the integrity of the study data). * Must weigh ≥ 6 kg at screening and at Day-1. * Must be at least 30 weeks of gestational age. * Physical examination must be acceptable to the investigator at screening and at Day -1. * Hemoglobin ≥ 8 g/dL at screening and at Day -1. * Serum calcium within age-appropriate normal ranges per the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines at screening and at Day -1 * Normal or clinically acceptable electrocardiogram (ECG) (12-lead reporting RR, PR, QRS, and QTc intervals) at screening and at Day -1. * Clinical laboratory tests that are acceptable to the investigator at screening and at Day -1.
Exclusion criteria
* Current or historic malignancy. * Cardiac ventricular arrhythmias within 28 days prior to screening. * A gastrointestinal disorder or surgery that could affect the absorption of drugs (eg, pyloric stenosis or any gut-shortening surgical procedure prior to screening). * A new onset of seizure or worsening of a pre-existing seizure disorder within 2 months prior to IP administration. * Major surgery (defined as any surgical procedure that involves general anesthesia or respiratory assistance) within 28 days prior to screening. * Hepatic impairment indicated by elevated levels of hepatic transaminase or bilirubin (aspartate aminotransferase (AST) ≥ 1.5 x upper limit of normal (ULN) OR alanine aminotransferase (ALT) ≥ 1.5 x ULN OR total bilirubin ≥ 1 x ULN per institutional laboratory range) at screening or Day-1. * History of prolongation of the QT interval (eg, congenital long QT interval, second or third degree heart block or other conditions which prolong the QT interval) * Corrected QT Interval (QTc) \> 500 ms during screening, using Bazett's formula * QTc ≥ 450 and ≤ 500 ms during screening, using Bazett's formula, unless written permission to enroll is provided by the investigator after consultation with a pediatric cardiologist * Known hypersensitivity to cinacalcet HCl or any of the excipients in cinacalcet HCl. * Use of grapefruit juice, herbal medications or potent CYP 3A4 inhibitors (eg, erythromycin, clarithromycin, ketokonazole, itraconazole) within the 14 days prior to enrollment and during the study. * Concurrent or within 28 days prior to enrollment use of medications that are predominantly metabolized by the enzyme CYP2D6 and have a narrow therapeutic index (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants such as desipramine and imipramine, and beta-blockers such as metoprolol or carvedilol). * Concurrent or within 28 days prior to enrollment use of medications that prolong QT interval (eg, sotalol, amiodarone, erythromycin, or clarithromycin). * Currently receiving treatment in another investigational device or drug study, or less than 90 days since ending treatment on another investigational device or drug study(s). * Other investigational procedures while participating in this study are excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Day 1 to day 30 | A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal • life threatening • requires in patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event. Treatment-related adverse events are those the investigator assessed as being possibly related to any study mandated activity (eg, administration of investigational product, protocol-required therapies, device(s) and/or procedure). Events of interest included acute pancreatitis, convulsions, drug related hepatic disorders, fractures, hypersensitivity, hypocalcemia, ischaemic heart disease, ventricular tachyarrhythmias, cardiac failure, and hypotension. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUCinf) for Cinacalcet | Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose | — |
| Maximum Observed Plasma Concentration (Cmax) of Cinacalcet | Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose | — |
| Time to Reach Maximum Observed Plasma Concentration of Cinacalcet (Tmax) | Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose | — |
| Terminal Half-life of Cinacalcet | Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose | The terminal half-life (T1/2) of cinacalcet associated with the slope of the terminal phase. |
| Area Under the Plasma Concentration Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) for Cinacalcet | Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose | — |
| Percent Change From Baseline in Total Calcium | Baseline (predose) and 2, 8, 12 and 48 hours post-dose. | — |
| Percent Change From Baseline in Albumin Corrected Calcium | Baseline (predose) and 2, 8, 12 and 48 hours post-dose. | — |
| Percent Change From Baseline in Ionized Calcium | Baseline (predose) and 2, 8, 12 and 48 hours post-dose. | — |
| Percent Change From Baseline in Intact Parathyroid Hormone | Baseline (predose) and at 2, 8, 12 and 48 hours post-dose. | — |
Countries
Germany, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 7 study centers in Belgium (1 site), Germany (1 site), the United Kingdom (2 sites), and the United States (3 sites). The first participant was enrolled 25 January 2011 and the last participant on 25 August 2015.
Pre-assignment details
Due to blood volume collection limitations in children, participants were randomized in a 1:1 ratio to one of the following 2 pharmacodynamic (PD) sampling sequences: 2, 8, and 48 hours postdose; or 2, 12, and 48 hours postdose.
Participants by arm
| Arm | Count |
|---|---|
| Cinacalcet 0.25 mg/kg Participants were to receive a single oral dose of 0.25 mg/kg cinacalcet on day 1. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Other | 2 |
Baseline characteristics
| Characteristic | Cinacalcet 0.25 mg/kg |
|---|---|
| Age, Continuous | 39.5 months STANDARD_DEVIATION 17.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 2 participants |
| Race/Ethnicity, Customized Black (or African American) | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Other | 3 participants |
| Race/Ethnicity, Customized White | 9 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Number of Participants With Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal • life threatening • requires in patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event. Treatment-related adverse events are those the investigator assessed as being possibly related to any study mandated activity (eg, administration of investigational product, protocol-required therapies, device(s) and/or procedure). Events of interest included acute pancreatitis, convulsions, drug related hepatic disorders, fractures, hypersensitivity, hypocalcemia, ischaemic heart disease, ventricular tachyarrhythmias, cardiac failure, and hypotension.
Time frame: Day 1 to day 30
Population: All participants who received at least 1 dose of cinacalcet.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Number of Participants With Adverse Events | Any adverse event (AE) | 3 participants |
| Cinacalcet 0.25 mg/kg | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Cinacalcet 0.25 mg/kg | Number of Participants With Adverse Events | AE leading to discontinuation of study drug | 0 participants |
| Cinacalcet 0.25 mg/kg | Number of Participants With Adverse Events | Fatal adverse events | 0 participants |
| Cinacalcet 0.25 mg/kg | Number of Participants With Adverse Events | Treatment-related adverse events | 1 participants |
| Cinacalcet 0.25 mg/kg | Number of Participants With Adverse Events | Adverse events of interest | 1 participants |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUCinf) for Cinacalcet
Time frame: Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
Population: Pharmacokinetics analysis set; The AUCinf value for one participant was excluded based on the goodness-of-fit (R²) value exclusion criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUCinf) for Cinacalcet | 11.3 hr*ng/mL | Standard Deviation 7.86 |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) for Cinacalcet
Time frame: Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
Population: Pharmacokinetics analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Area Under the Plasma Concentration Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) for Cinacalcet | 11.8 hr*ng/mL | Standard Deviation 8.74 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Cinacalcet
Time frame: Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
Population: Pharmacokinetics analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Maximum Observed Plasma Concentration (Cmax) of Cinacalcet | 2.83 ng/mL | Standard Deviation 1.98 |
Secondary
Percent Change From Baseline in Albumin Corrected Calcium
Time frame: Baseline (predose) and 2, 8, 12 and 48 hours post-dose.
Population: Due to the randomization to 1 of 2 sampling sequences not all participants had PD samples taken at every time point. n indicates participants with non-missing data at the time point of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Albumin Corrected Calcium | 8 hours post-dose (n = 5) | -7.12 percent change | Standard Deviation 6.71 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Albumin Corrected Calcium | 2 hours post-dose (n = 9) | -4.01 percent change | Standard Deviation 7.11 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Albumin Corrected Calcium | 12 hours post-dose (n = 5) | -4.24 percent change | Standard Deviation 1.7 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Albumin Corrected Calcium | 48 hours post-dose (n = 6) | -4.10 percent change | Standard Deviation 5.75 |
Secondary
Percent Change From Baseline in Intact Parathyroid Hormone
Time frame: Baseline (predose) and at 2, 8, 12 and 48 hours post-dose.
Population: Due to the randomization to 1 of 2 sampling sequences not all participants had PD samples taken at every time point. n indicates participants with non-missing data at the time point of interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Intact Parathyroid Hormone | 2 hours post-dose (n = 9) | -10.80 percent change |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Intact Parathyroid Hormone | 8 hours post-dose (n = 5) | -29.6 percent change |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Intact Parathyroid Hormone | 12 hours post-dose (n = 5) | 29.40 percent change |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Intact Parathyroid Hormone | 48 hours post-dose (n = 9) | -5.40 percent change |
Secondary
Percent Change From Baseline in Ionized Calcium
Time frame: Baseline (predose) and 2, 8, 12 and 48 hours post-dose.
Population: Due to the randomization to 1 of 2 sampling sequences not all participants had PD samples taken at every time point. n indicates participants with non-missing data at the time point of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Ionized Calcium | 2 hours post-dose (n = 9) | -1.77 percent change | Standard Deviation 3.55 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Ionized Calcium | 8 hours post-dose (n = 4) | -4.20 percent change | Standard Deviation 3.83 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Ionized Calcium | 12 hours post-dose (n = 4) | -4.15 percent change | Standard Deviation 10.12 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Ionized Calcium | 48 hours post-dose (n = 6) | -1.45 percent change | Standard Deviation 4.8 |
Secondary
Percent Change From Baseline in Total Calcium
Time frame: Baseline (predose) and 2, 8, 12 and 48 hours post-dose.
Population: Due to the randomization to 1 of 2 sampling sequences not all participants had PD samples taken at every time point. n indicates participants with non-missing data at the time point of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Total Calcium | 2 hours post-dose (n = 11) | -4.33 percent change | Standard Deviation 6.82 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Total Calcium | 8 hours post-dose (n = 5) | -6.38 percent change | Standard Deviation 5.12 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Total Calcium | 12 hours post-dose (n = 6) | -6.63 percent change | Standard Deviation 5.05 |
| Cinacalcet 0.25 mg/kg | Percent Change From Baseline in Total Calcium | 48 hours post-dose (n = 8) | -4.54 percent change | Standard Deviation 5.12 |
Secondary
Terminal Half-life of Cinacalcet
The terminal half-life (T1/2) of cinacalcet associated with the slope of the terminal phase.
Time frame: Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
Population: Pharmacokinetics analysis set; The T1/2 value for one participant was excluded based on the goodness-of-fit (R²) value exclusion criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Terminal Half-life of Cinacalcet | 3.70 hours | Standard Deviation 2.57 |
Secondary
Time to Reach Maximum Observed Plasma Concentration of Cinacalcet (Tmax)
Time frame: Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
Population: Pharmacokinetics analysis set
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Cinacalcet 0.25 mg/kg | Time to Reach Maximum Observed Plasma Concentration of Cinacalcet (Tmax) | 1.0 hours | Full Range 0.82 |