Clinical Trial Results:
A Phase 2, Open-Label, Single-Arm, Multidose Study to Investigate the Effects of Orteronel on the QT/QTc Interval in Patients with Metastatic Castration-Resistant Prostate Cancer
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Summary
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EudraCT number |
2012-000136-26 |
Trial protocol |
GR IE FR |
Global end of trial date |
21 Jan 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
04 May 2016
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First version publication date |
04 May 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 |
C21012
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01549951 | ||
WHO universal trial number (UTN) |
U1111-1179-5656 | ||
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Sponsors
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Sponsor organisation name |
Millennium Pharmaceuticals, Inc.
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Sponsor organisation address |
61 Aldwych, London, United Kingdom, WC2B 4AE
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Public contact |
Study Manager, Millennium Medical and Drug Information Center, 001 866-835-2233, GlobalOncologyMedinfo@takeda.com
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Scientific contact |
Study Manager, Millennium Medical and Drug Information Center, 001 866-835-2233, GlobalOncologyMedinfo@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Jun 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 |
21 Jan 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 purpose of this phase 2, open-label, single-arm, multidose, multicenter study is to investigate the effects of Orteronel plus Prednisone on the QT/QTc interval in patients with Metastatic Castration-Resistant Prostrate Cancer
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 May 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
3 Years | ||
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 |
France: 20
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Country: Number of subjects enrolled |
United States: 16
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Country: Number of subjects enrolled |
Canada: 7
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Country: Number of subjects enrolled |
Greece: 4
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Country: Number of subjects enrolled |
Ireland: 2
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Country: Number of subjects enrolled |
Romania: 1
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Worldwide total number of subjects |
50
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EEA total number of subjects |
27
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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) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
18
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From 65 to 84 years |
32
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects took part in the study at 16 investigative sites in Canada, France, Greece, Ireland, Romania, and the United States from 29 May 2012 to 21 January 2015. | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
Male subjects with a historical diagnosis of metastatic castration-resistant prostate cancer (mCRPC) were enrolled in this single arm study to receive orteronel 400 milligram (mg) along with prednisone 5 mg twice daily for 28 days in each treatment cycle. | ||||||||||||||||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||
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Arms
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Arm title
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Orteronel + Prednisone | ||||||||||||||||||||||
Arm description |
Orteronel 400 mg, tablets, orally, twice daily along with prednisone 5 mg, tablets, orally, twice daily for 2 treatment cycles of 28 days each. Gonadotropin-releasing hormone analogue therapy was supplied as a commercially available dosage formulation. | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Orteronel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Orteronel 400 mg, tablets, orally, twice daily for 2 treatment cycles of 28 days each.
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Investigational medicinal product name |
Prednisone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Prednisone 5 mg, tablets, orally, twice daily for 2 treatment cycles of 28 days each.
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Baseline characteristics reporting groups
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Reporting group title |
Orteronel + Prednisone
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Reporting group description |
Orteronel 400 mg, tablets, orally, twice daily along with prednisone 5 mg, tablets, orally, twice daily for 2 treatment cycles of 28 days each. Gonadotropin-releasing hormone analogue therapy was supplied as a commercially available dosage formulation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Orteronel + Prednisone
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Reporting group description |
Orteronel 400 mg, tablets, orally, twice daily along with prednisone 5 mg, tablets, orally, twice daily for 2 treatment cycles of 28 days each. Gonadotropin-releasing hormone analogue therapy was supplied as a commercially available dosage formulation. | ||
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End point title |
Maximum Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method [1] | ||||||||
End point description |
Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 1 minute) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia’s formula (QTcF = QT divided by cube root of RR). Results of change in QTcF analyzed from 12-lead ECGs performed at each time point were averaged for analysis and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. ECG analysis population was defined as all subjects with at least 1 available baseline and at least 1 on-treatment ECG who received at least 1 dose of any study drug.
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End point type |
Primary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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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: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Change From Baseline in QTc Based on the Bazett Correction (QTcB) Method, PR, QRS and Uncorrected QT Interval | ||||||||||||||||
End point description |
Triplicate 12-lead ECG measurements (each recording separated by approximately 1 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Bazette’s formula (QTcB = QT divided by square root of RR). Results of change in QTcB, PR, QRS and uncorrected QT analyzed from 12-lead ECGs performed at each time point were averaged for analysis and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. ECG analysis population was defined as all subjects with at least 1 available baseline and at least 1 on-treatment ECG who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Changes From Baseline in Heart Rate | ||||||||
End point description |
Triplicate 12-lead Electrocardiogram (ECG) measurements were performed and average was calculated. Supine heart rate was measured as beats per minute (bpm). Results of change in heart rate analyzed from 12-lead ECGs performed at each time point were averaged for analysis and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. ECG analysis population was defined as all subjects with at least 1 available baseline and at least 1 on-treatment ECG who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Reporting Change From Baseline in ECG Morphology | ||||||||||||||
End point description |
Subjects with incidence of ECG morphology abnormalities were observed. Types of abnormalities included appearance of abnormal U waves,T waves inversion,elevation of ST segment,depression of ST segment,second or third degree heart block,right or left bundle branch block,atrial fibrillation/flutter,and myocardial infarction.New morphological changes were observed in abnormal U waves,depression of ST segment,and T waves inversion.Here,'new' refers to change not present at baseline, ie, at any evaluation predose, and only seen postbaseline.Results of change in ECG morphology analyzed from 12-leadECG at each time point were averaged for analysis and a maximum across all post-dosing time points was used.Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing.ECG analysis population was defined as all subjects with at least 1 available baseline and at least 1 on-treatment ECG who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
AUC(0-6): Area Under the Plasma Concentration-Time Curve From Time 0 to 6 Hours Postdose for Orteronel and M-I metabolite | ||||||||||||
End point description |
AUC(0-6) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau]), where tau is the length of the dosing interval - 6 hours in this study). Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. Pharmacokinetic (PK) population was defined as all subjects who had sufficient dosing data and plasma concentration-time data to permit calculations of PK parameters.
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End point type |
Secondary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Correlation Between the QTcF Change From Baseline and Plasma Concentrations of Orteronel | ||||||||
End point description |
Coefficient of correlation was measured using linear mixed effects model for the association between two variables; change from baseline versus the plasma concentration. Subjects’s effects on the intercept and plasma concentration slope were included in the model as random effects terms. Plasma concentrations were re scaled for model convergence. Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. ECG analysis population was defined as all subjects with at least 1 available baseline and at least 1 on-treatment ECG who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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| No statistical analyses for this end point | |||||||||
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End point title |
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I metabolite | ||||||||||||||||
End point description |
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. PK population was defined as all subjects who had sufficient dosing data and plasma concentration-time data to permit calculations of PK parameters.
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End point type |
Secondary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I metabolite | ||||||||||||||||
End point description |
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. PK population was defined as all subjects who had sufficient dosing data and plasma concentration-time data to permit calculations of PK parameters.
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End point type |
Secondary
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End point timeframe |
Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Number of Subjects Reporting One or More Treatment-emergent Adverse Events | ||||||||
End point description |
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Safety analysis set was defined as all subjects who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to 30 days after last dose of study drug (Day 86)
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Reporting Clinically Significant Abnormalities in Vital Signs | ||||||||
End point description |
The number of subjects with any clinically significant abnormalities in vital signs collected throughout study. Vital signs included body temperature (oral), sitting blood pressure (after the subject has rested for at least 5 minutes), and pulse (bpm). Safety analysis set was defined as all subjects who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to 30 days after last dose of study drug (Day 86)
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Reporting Clinically Significant Abnormalities in Laboratory Values | ||||||||
End point description |
The number of subjects with any clinically significant abnormalities in safety laboratory values collected throughout study. Safety analysis set was defined as all subjects who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to 30 days after last dose of study drug (Day 86)
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Reporting Clinically Significant Abnormalities in Physical Findings | ||||||||
End point description |
Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10). Safety analysis set was defined as all subjects who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to 30 days after last dose of study drug (Day 86)
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Reporting Clinically Significant Abnormalities in ECG | ||||||||
End point description |
The number of subjects who reported clinically significant abnormalities in ECG were measured throughout study. ECGs were performed after the subject had been supine for at least 10 minutes. Safety analysis set was defined as all subjects who received at least 1 dose of any study drug.
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End point type |
Secondary
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End point timeframe |
Baseline up to 30 days after last dose of study drug (Day 86)
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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 |
Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days after the last dose of double-blind study drug (Day 86).
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Adverse event reporting additional description |
At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the subject or observed by the investigator was recorded, irrespective of the relation to study treatment.
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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 |
15.0
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Reporting groups
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Reporting group title |
Orteronel + Prednisone
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Reporting group description |
Orteronel 400 mg, tablets, orally, twice daily along with prednisone 5 mg, tablets, orally, twice daily for 2 treatment cycles of 28 days each. Gonadotropin-releasing hormone analogue therapy was supplied as a commercially available dosage formulation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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 | |||
