Clinical Trial Results:
An Open-label, Single-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Cinacalcet HCl in Pediatric Subjects Aged 28 Days to less than 6 Years With Chronic Kidney Disease Receiving Dialysis
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Summary
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EudraCT number |
2009-017999-25 |
Trial protocol |
GB BE DE Outside EU/EEA |
Global end of trial date |
23 Sep 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Apr 2016
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First version publication date |
08 Apr 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
20090005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01290029 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Amgen, Inc.
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Sponsor organisation address |
One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
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Public contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Scientific contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000078-PIP01-07 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Sep 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Sep 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and other local regulations/ guidelines. The study and all amendments were reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) at each center. Before any study-specific screening procedures were performed, written informed consent was obtained from the subject’s parent or legally acceptable representative. The investigator was responsible for providing the subject’s legally acceptable representative an adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study.
A conservative single, oral dosing strategy of 0.25 mg/kg cinacalcet in pediatric subjects aged 28 days to less than 6 years old was implemented. This dose is approximately half the adult starting dose on a mg/kg basis, and is lower than the mean dose of 0.39 mg/kg previously studied in 12 subjects age 6 to < 18 years in Study 20030227. To monitor subject safety, serum calcium and phosphorus were monitored throughout the study. To minimize blood loss due to the study, the blood volume required for safety laboratory and PK assessment were minimized and the number of collections reduced to the minimum requirement to enable the endpoints of this study to be analyzed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Jan 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
United States: 7
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Worldwide total number of subjects |
14
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EEA total number of subjects |
7
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
3
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Children (2-11 years) |
11
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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. | ||||||||||||
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Pre-assignment
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Screening details |
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. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Cinacalcet 0.25 mg/kg | ||||||||||||
Arm description |
Participants received a single oral dose of 0.25 mg/kg cinacalcet on day 1. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Cinacalcet
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Investigational medicinal product code |
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Other name |
Sensipar®, Mimpara®
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received single oral doses of 0.25 mg/kg cinacalcet.
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Baseline characteristics reporting groups
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Reporting group title |
Cinacalcet 0.25 mg/kg
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Reporting group description |
Participants received a single oral dose of 0.25 mg/kg cinacalcet on day 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cinacalcet 0.25 mg/kg
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Reporting group description |
Participants received a single oral dose of 0.25 mg/kg cinacalcet on day 1. | ||
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End point title |
Number of Participants with Adverse Events [1] | ||||||||||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Day 1 to day 30
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analyses were not performed in this open-label single-arm study. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Area Under the Plasma Concentration Time Curve from Time Zero to Time of Last Quantifiable Concentration (AUClast) for Cinacalcet | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration Time Curve from Time Zero to Infinity (AUCinf) for Cinacalcet | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
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| Notes [2] - AUCinf values for one subject were excluded based on the goodness-of-fit (R²) value < 0.8. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Observed Plasma Concentration (Cmax) of Cinacalcet | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Reach Maximum Observed Plasma Concentration of Cinacalcet (Tmax) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
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| No statistical analyses for this end point | |||||||||
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End point title |
Terminal Half-life of Cinacalcet | ||||||||
End point description |
The terminal half-life (T1/2) of cinacalcet associated with the slope of the terminal phase.
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours post-dose
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| Notes [3] - T1/2 values for one subject were excluded based on the goodness-of-fit (R²) value < 0.8. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percent Change from Baseline in Intact Parathyroid Hormone | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and at 2, 8, 12 and 48 hours post-dose.
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percent Change from Baseline in Total Calcium | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 2, 8, 12 and 48 hours post-dose.
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percent Change from Baseline in Albumin Corrected Calcium | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 2, 8, 12 and 48 hours post-dose.
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percent Change from Baseline in Ionized Calcium | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (predose) and 2, 8, 12 and 48 hours post-dose.
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| No statistical analyses for this end point | |||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
30 Days
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Adverse event reporting additional description |
Adverse Events
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.0
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Reporting groups
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Reporting group title |
Cinacalcet 0.25 mg/kg
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Reporting group description |
Participants received a single oral dose of 0.25 mg/kg cinacalcet on day 1. | ||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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18 Jun 2010 |
- This protocol was amended in response to a request by the MHRA to provide detailed procedures for reporting and recording adverse events in accordance with the EU Clinical Trials Directive.
Specifically, details on adverse event reporting procedures were added to Section 9.3. |
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20 Aug 2010 |
- This protocol was amended to include the European Medicines Agency (EMEA) Pediatric Committee (PDCO) requirement for ionized calcium, ie, total calcium, albumin corrected calcium, and ionized calcium; updated corresponding sections as appropriate.
- Changes were made to the inclusion/exclusion criteria to address comments from the Medicines for Children Research Network (MCRN) in the United Kingdom.
o Removed inclusion criterion requirement to be hemodynamically and neurologically stable for at least 4 weeks postpartum if < 6 months old
o Changed inclusion criterion hemoglobin requirement to ≥ 8 g/dL at screening and at day -1.
o Defined major surgery under exclusion criteria as any surgical procedure requiring general anesthesia or respiratory assistance. |
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04 Jan 2011 |
- This protocol was amended in response to comments by the FDA as follows:
o Secondary hyperparathyroidism was added to the CKD diagnosis in the inclusion criteria.
o The day 1, 4-hour postdose blood collection was changed to 2 hours postdose and a 12-hour, postdose blood collection was added for subjects weighing ≥ 7.5 kg. Blood sampling procedures and volumes for calcium and iPTH were updated accordingly.
- Serum calcium laboratory results were clarified as ≥ 2.1 mmol/L or within normal ranges at screening and day -1.
- Statistical analyses for the pharmacokinetics parameters AUC, t1/2, Cmax, and tmax were clarified.
- The US was added as a location for new study centers and the IRB was added where appropriate.
- Schedule of Assessments and footnotes were updated. |
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11 Apr 2011 |
- This protocol was amended in response to FDA comments and clarifications made by the study team. Since hemodialysis can change a subject’s clinical chemistry test results, blood sample collections were modified to be concurrent with hemodialysis.
Changes included the following:
o The pharmacodynamics blood sample collection was changed to include randomization into 2 pharmacodynamic sampling sequences (a and b) within each age group. Six subjects were randomized in a 1:1 ratio into 1 of the following pharmacodynamics sampling sequences:
a) approximately day 1: -2, 8 and 48 hours postdose; or
b) approximately day 1: -2, 12 and 48 hours postdose.
Blood collection volumes were updated as appropriate.
o If the safety blood sample collection was concurrent with or within 4 hours after hemodialysis, only albumin, calcium, and iPTH levels were required to be tested for that time point.
o The sample size consideration section was updated.
- Serum calcium requirement in inclusion criteria was changed to within normal ranges at screening and day -1.
- A description of cinacalcet investigational product was added.
- Schedule of Assessments and footnotes were updated. |
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14 Jun 2011 |
- The protocol was amended to add randomization by IVRS to assign subjects to 1 of the 2 pharmacodynamic sampling sequences and revise the reporting period for adverse event collection to begin following initiation of investigational product.
- Due to the addition of the IVRS, the time of enrollment was redefined as the time of randomization.
- With reference to the ICF, the term “subject” was updated to “subject’s parent or legally acceptable representative (SPoLAR)” and “assent” was removed throughout the protocol. Information regarding the treatment of hypocalcemia was moved to the Concomitant Therapy section.
- Stopping rules were clarified to apply at the age group or study level. The use of CTCAE v4.0 was clarified.
- Sites were required to report dialysis and dialysate information for subjects undergoing dialysis on study day -1 through day 4.
- Wording changes and clarifications were made throughout the document as appropriate. |
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28 Oct 2013 |
- This protocol was amended to comply with DMC recommendations after review of the cinacalcet program following a fatality in the pediatric Study 20070208, which includes:
o Revision of the inclusion/exclusion criteria to exclude subjects with prolonged QTc interval, corrected QTc (Bazett’s) > 500 ms, or QTc (Bazett’s) ≥ 450 ms and ≥ 500 ms during screening; exclusion of subjects who used drugs which may prolong QTc interval within 28 days prior to enrollment.
o Addition of an updated safety summary from the cinacalcet pediatric program including a description of the fatality in Study 20070208.
o Addition of a second follow-up phone call for all subjects at day 30 for assessment of serious adverse events.
- Based on available study data showing no age-related differences in safety and pharmacokinetics profile, the Age Group 28 days to < 3 years and the Age Group ≥ 3 years to < 6 years were merged into a single age group comprising approximately 12 subjects.
Appropriate changes were made throughout the document.
- Updated inclusion criterion to “age-appropriate” serum calcium normal ranges at screening and day -1.
- Section on overdosing effects of cinacalcet was added.
- Specified the Safety Analysis Set for the analysis of all endpoints.
- Updated statistical analysis of pharmacokinetics parameters. |
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20 May 2015 |
- To align with other, ongoing, pediatric clinical trials of cinacalcet, the following changes were made:
o Modified the exclusion criterion from a history of seizures to new onset of seizure or worsening of a pre-existing seizure disorder within 2 months prior to investigational product administration.
o Updated the Investigational Product Dosage and Administration to clarify the water preparation was only for administration through nasogastric or gastric tubes, while the syrup formulation could be used for either oral or nasogastric/gastric tube administration.
- The pharmacokinetics and pharmacodynamics endpoints were updated to align with the Study 20090005 SAP and PIP Key Elements Form. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
