Compare Safety and Efficacy of BIBF 1120 Versus Sunitinib.
- Registration Number
- NCT01024920
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
Compare safety and efficacy of BIBF 1120 versus sunitinib in patients with advanced RCC and to investigate the effects of BIBF 1120 on the heart rate (HR) corrected QT interval (QTcF).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 99
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Nintedanib (BIBF 1120) BIBF 1120 Non-marketed substance: Twice daily oral doses of 200mg BIBF 1120 given continuously. sunitinib sunitinib Marketed substance: Once a day oral doses of 50mg sunitinib given in repeated 6 week cycles: 4 weeks active, 2 weeks rest.
- Primary Outcome Measures
Name Time Method Probability Rates of Progression-free Survival at 9 Months At 9 months after randomisation. Progression free survival rate at 9 months is the estimated probability of being alive and not having progressive disease at 9 months after randomisation.
Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria version 1.1 (RECIST v1.1), at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started together with an absolute increase in the sum of the longest diameters of at least 5 mm, or the appearance of one or more new lesions.
Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication.Time-matched Change From Baseline to Day 15 in QTcF (QT Interval Corrected by the Fridericia Formula) at 0 Hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h After Dosing of Nintedanib (BIBF 1120) At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 15. Baseline (Day -1) values were taken at exactly the same time points as on Day 15. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate by the Fridericia formula. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 15 in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 15 obtained at time t minus baseline QTcF measurement at time t. 0 h is 5 min prior to dosing on Day 15.
Time-matched change from baseline to Day 15 in QTcF was modelled using a linear mixed-effects model for repeated measures which included 'time' as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals at 0 h,1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h and 12 h after dosing of nintedanib on Day 15 of are reported.
- Secondary Outcome Measures
Name Time Method Duration of Objective Response From the time of first objective response to the time of disease progression or death (whichever comes first), up to 3 years. Duration (months) of objective response was measured from the time of first objective response to the time of disease progression (by RECIST Version 1.1) or death, whichever occurred first.
Objective response was defined as complete response (CR, the disappearance of all target and non-target lesions and no new lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum of the longest diameters and no new lesions) as determined by RECIST Version 1.1.
Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication. The Kaplan-Meier method was used to calculate the estimates.Overall Survival From randomisation to death, up to 3 years. Overall survival was calculated as the time (months) from randomisation to death. Patients for whom there was no evidence of death at the time of analysis were censored on the date that they were last known to have been alive.
The Kaplan-Meier method was used to calculate the estimates.Objective Response According to RECIST Criteria From the start of study until the cut-off date for 3 year efficacy analysis, up to 3 years. Objective response was defined as complete response (CR, the disappearance of all target and non-target lesions and no new lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum of the longest diameters and no new lesions) as determined by RECIST Version 1.1. Numbers of participants with objective response are reported.
Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication.Time to Progression From randomisation up to objective tumour progression, up to 3 years. Time to progression is defined as the time period from randomisation to objective tumour progression. Patients with no progression (by RECIST Version 1.1) were censored at the date of the last evaluable imaging.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started together with an absolute increase in the sum of the longest diameters of at least 5 mm, or the appearance of one or more new lesions.
Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication. The Kaplan-Meier method was used to calculate the estimates.Progression Free Survival (PFS) From the start of study until the cut-off date for 3 year efficacy analysis, up to 3 years. Progression free survival (PFS) from randomisation to the occurrence of disease progression (by RECIST Version 1.1) or death, whichever occurred first.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started together with an absolute increase in the sum of the longest diameters of at least 5 mm, or the appearance of one or more new lesions.
Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication.
The Kaplan-Meier method was used to calculate the estimates.Averaged Time-matched Changes From Baseline in QT Interval (Electrocardiogram (ECG) Interval From the Beginning of the QRS Complex to the End of the T Wave) Over 1 h to 12 h After Dosing on Days 1 and 15 of Treatment Cycle 1 At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Averaged time-matched QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) changes from baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120) to Day 1 (first drug dose nintedanib (BIBF 1120)) and to Day 15 (steady state) over 1 to 12 hours was evaluated using a t-test for paired observation. The mean differences between post-treatment values (Days 1 and 15) and baseline (Day -1) along with two-sided 90% confidence limits are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15.Time to Treatment Failure From randomisation up to objective tumour progression, up to 3 years. Time to treatment failure was defined as the time from randomisation to objective tumour progression (by RECIST Version 1.1), death, global deterioration of health status requiring treatment discontinuation, or start of new anticancer treatment, whichever came first. Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication.The Kaplan-Meier method was used to calculate the estimates.
Time-Matched Change From Baseline in QTcF Interval at the Time of Each Patient's Maximum Plasma Concentration of BIBF 1202-glucuronide (a Nintedanib (BIBF 1120) Metabolite), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QTcF measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in QTcF' at the time of the participant's maximum BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline values were taken at exactly the same time points as on Day 15.Time-Matched Change From Baseline in QT Interval at the Time of Each Patient's Maximum Plasma Concentration of BIBF 1202 (a Nintedanib (BIBF 1120) Metabolite), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description. QT interval is the (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QT measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in QT' at the time of the participant's maximum BIBF 1202 (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Time-Matched Change From Baseline in QT Interval at the Time of Each Patient's Maximum Plasma Concentration BIBF 1202-glucuronide (a Nintedanib (BIBF 1120) Metabolite), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. QT interval is the (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QT measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in QT' at the time of the participant's maximum BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Time-matched Change From Baseline to Day 1 in QTcF (QT Interval Corrected by the Fridericia Formula) at 1 Hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h After Dosing of Nintedanib (BIBF 1120) At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 of treatment Cycle 1. Baseline (Day -1) values were taken at exactly the same time points as on Day 1. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate by the Fridericia formula. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 obtained at time t minus baseline QTcF measurement at time t.
Time-matched change from baseline to Day 1 in QTcF was modelled using a linear mixed-effects model for repeated measures which included 'time' as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals at 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h and 12 h after dosing of nintedanib on Day 1 are reported.Average Time-matched Changes From Baseline in QTcF Interval Over 1 h to 12 h After Dosing on Days 1 and 15 of Treatment Cycle 1 At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description. Average time-matched in QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) changes over 1 to 12 hours was evaluated using a t-test for paired observation. The mean differences between post-treatment values (Days 1 and 15) and baseline (Day -1) along with two-sided 90% confidence limits are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15.Time-Matched Change From Baseline in QTcF Interval at the Time of Each Patient's Maximum Plasma Concentration of BIBF 1202 (a Nintedanib (BIBF 1120) Metabolite), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QTcF measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in QTcF' at the time of the participant's maximum BIBF 1202 (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Time-matched Changes From Baseline to Day 15 in QT Interval at 0 Hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h After Dosing of Nintedanib (BIBF 1120) At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 15. Baseline (Day -1) values were taken at exactly the same time points as on Day 15. QT interval is the electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 15 in QT at time t was defined as the QT measurement following administration of nintedanib on Day 15 obtained at time t minus baseline QT measurement at time t. 0 h is 5 min prior to dosing on Day 15.
Time-matched change from baseline to Day 15 in QT was modelled using a linear mixed-effects model for repeated measures which included 'time' as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals at 0 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h and 12 h after dosing of nintedanib on Day 15 of Cycle 1are reported.Time-Matched Change From Baseline in Heart Rate (HR) at the Time of Each Patient's Maximum Plasma Concentration of BIBF 1202-glucuronide (a Nintedanib (BIBF 1120) Metabolite), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of treatment cycle 1. Continues in the description. Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in HR at time t was defined as the HR measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline HR measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in HR' at the time of the participant's maximum BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15.Time-matched Change From Baseline in QTcF Interval (QT Interval Corrected by the Fridericia Formula) at the Time of Each Participant's Maximum Plasma Concentration of Nintedanib (BIBF 1120), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QTcF measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in QTcF' at the time of the participant's maximum nintedanib plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Time-matched Changes From Baseline to Day 1 in QT Interval at 1 Hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h After Dosing of Nintedanib (BIBF 1120) At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1. Baseline (Day -1) values were taken at exactly the same time points as on Day 1. QT interval is the electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 obtained at time t minus baseline QT measurement at time t.
Time-matched change from baseline to Day 1 in QT was modelled using a linear mixed-effects model for repeated measures which included 'time' as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals at 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h and 12 h after dosing of nintedanib on Day 1 are reported.Frequency of Patients With Maximum Time-Matched QTcF Interval Change From Baseline Categorized by Magnitude of Change, Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula.
Number of patients with maximum time-matched change from baseline in the QTcF interval observed at each point in time, i.e., 9 time points on Day 1 and 10 timepoints on Day 15 is reported. 3 categories of individual QTcF increases from baseline to maximum value were defined:
\<= 30 milliseconds (ms)
\> 30 to 60 milliseconds (ms)
\> 60 milliseconds (ms) Changes more than 60 ms in the QTcF interval represent notable changes. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Time-Matched Change From Baseline in QT Interval at the Time of Each Patient's Maximum Plasma Concentration of Nintedanib (BIBF 1120), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. QT interval is the (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QT measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in QT' at the time of the participant's maximum nintedanib plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15.Time-Matched Heart Rate (HR) Changes From Baseline to Day 1 at 1 Hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h After Dosing of Nintedanib (BIBF 1120) At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1. Baseline (Day -1) values were taken at exactly the same time points as on Day 1. Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib (BIBF 1120) at time t. Time-matched change from baseline to Day 1 in HR at time t was defined as the HR measurement following administration of nintedanib (BIBF 1120) on Day 1 obtained at time t minus baseline HR measurement at time t.
Time-matched change from baseline to Day 1 in HR was modelled using a linear mixed-effects model for repeated measures which included 'time' as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals at 0 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h and 12 h after dosing of nintedanib (BIBF 1120) on Day 1 are reported.Time-Matched Change From Baseline in Heart Rate (HR) at the Time of Each Patient's Maximum Nintedanib (BIBF 1120) Plasma Concentration, Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in HR at time t was defined as the HR measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline HR measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in HR' at the time of the participant's maximum nintedanib plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Frequency of Patients With Maximum Time-Matched QT Interval (Electrocardiogram (ECG) Interval From the Beginning of the QRS Complex to the End of the T Wave) Change From Baseline Categorized by Magnitude of Change, Days 1 and 15 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. Number of patients with maximum time-matched change from baseline in the QT interval observed at each point in time, i.e., 9 time points on Day 1 and 10 timepoints on Day 15 is reported. 3 categories of individual QTcF increases from baseline to maximum value were defined:
\<= 30 milliseconds (ms)
\> 30 to 60 milliseconds (ms)
\> 60 milliseconds (ms) Changes more than 60 ms in the QT interval represent notable changes. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Number of Participants With Adverse Events Leading to Discontinuation of Trial Drug From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months. Number of participants with Adverse Events which lead to discontinuation of trial medication drug is reported for each treatment arm.
Duration of Hospital Stays Due to Adverse Events Requiring or Prolonging Hospitalisation From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months. Duration of hospitalisation in days for each treatment arm is reported for those patients who experienced adverse events which required or prolonged hospitalisation (of the patients).
Time-Matched Heart Rate (HR) Changes From Baseline to Day 15 at 0 Hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h After Dosing of Nintedanib (BIBF 1120) At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 15. Baseline (Day -1) values were taken at exactly the same time points as on Day 15. Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib (BIBF 1120) at time t. Time-matched change from baseline to Day 15 in HR at time t was defined as the HR measurement following administration of nintedanib (BIBF 1120) on Day 15 obtained at time t minus baseline HR measurement at time t. 0 h is 5 min prior to dosing on Day 15.
Time-matched change from baseline to Day 15 in HR was modelled using a linear mixed-effects model for repeated measures which included 'time' as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals at 0 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 10 h and 12 h after dosing of nintedanib (BIBF 1120) on Day 15 of Cycle 1 are reported.Time-Matched Change From Baseline in Heart Rate (HR) at the Time of Each Patient's Maximum Plasma Concentration of BIBF 1202 (a Nintedanib (BIBF 1120) Metabolite), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in HR at time t was defined as the HR measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline HR measurement at time t.
For each participant 'Time-matched change from baseline to Day 1 (Day 15) in HR' at the time of the participant's maximum BIBF 1202 (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Averaged Time-Matched Heart Rate (HR) Change From Baseline Over 1 to 12 Hours, Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15. Averaged time-matched heart rate changes from baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) to Day 1 (first drug dose nintedanib (BIBF 1120)) and to Day 15 (steady state) over 1 to 12 hours was evaluated using a t-test for paired observation. The mean differences between post-treatment values (Days 1 and 15) and baseline (Day -1) along with two-sided 90% confidence limits are reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15.Number of Participants With New Onset of QTcF> 470 to 500 Milliseconds (ms), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula.
Number of participants with new onset of QTcF\> 470 to 500 milliseconds (ms) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Absolute Values at Baseline (Day -1) and Day 1 and Changes From Baseline to Day 1 at Each Point in Time in QRS Interval At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1. Baseline (Day -1) values were taken at exactly the same time points as on Day 1. QRS interval is an electrocardiogram (ECG) interval and is the time interval from the onset to the end of the QRS complex (combination of the Q wave, R wave and S wave). The normal QRS duration is less than 120 milliseconds (ms). Absolute values and changes from baseline (Day-1 prior to the first dosing of nintedanib) to Day 1 (first drug dose of nintedanib (BIBF 1120)) at each point in time i.e., 10 time points from 0 to 12 in the QRS interval are reported.
Number of Participants With Adverse Events Leading to Dose Reduction From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months. Number of participants who experienced Adverse Events which led to dose reduction of the trial medication is reported for each treatment arm.
Number of Participants With New (Not Present at Any Time Pre-dose) Onset of QTcF ≤450 Milliseconds (ms), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula.
Number of participants with new onset (not present at any time pre-dose) of QTcF ≤450 milliseconds (ms) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Number of Participants With New (Not Present at Any Time Pre-dose) Onset of QTcF >450 to 470 Milliseconds (ms), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula.
Number of participants with new onset of QTcF \>450 to 470 milliseconds (ms) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Frequency of Adverse Events Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0 From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months. The number of participants who experienced adverse events graded according to NCI CTCAE version 3.0, is reported below.The maximum grade of adverse event intensity for each type of treatment-related adverse event was recorded for each patient.
Grade 1 - Mild AE Grade 2 - Moderate AE Grade 3 - Severe AE Grade 4 - Life-threatening or disabling AE Grade 5 - Death related to AEFrequency of Patients With Possible Clinically Significant Abnormal Lab Values From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months. Number of patients with possible clinically significant abnormal lab values for the lab parameters alkaline phosphatase, activated partial thromboplastin time (APTT), creatinine, haemoglobin, prothrombin time (PT)-international normalized ratio (INR), potassium, lymphocytes, sodium, neutrophils, platelets, aspartate amino transferase (AST), alanine aminotransferase (ALT), bilirubin and white blood cell count is reported. Only lab values with CTCAE rule for possible clinical significance are displayed.
Number of Participants With New (Not Present at Any Time Pre-dose) Onset of QTcF> 500 Milliseconds (ms) (Notable Prolongation), Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description. QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula.
Number of participants with new onset of QTcF\> 500 milliseconds (ms) (notable prolongation) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Number of Participants With New (Not Present at Any Time Pre-dose) Onset of QT (Electrocardiogram (ECG) Interval From the Beginning of the QRS Complex to the End of the T Wave) > 500 ms (Notable Prolongation), Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description. Number of participants with new onset of QT (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave)\> 500 milliseconds (ms) (notable prolongation) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported.
Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Absolute Values at Baseline (Day -1) and Day 1 and Changes From Baseline to Day 1 at Each Point in Time in PR Interval At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1. Baseline (Day -1) values were taken at exactly the same time points as on Day 1. The PR interval is an electrocardiogram (ECG) interval and is the time from the onset of the P wave to the start of the QRS complex (combination of the Q wave, R wave and S wave). It reflects conduction through the atrioventricular node (AV) node. The normal PR interval is between 120 - 200 milliseconds (ms) (0.12-0.20s) in duration. Absolute values at baseline (Day-1 prior to the first dosing of nintedanib) and at Day 1 (first drug dose of nintedanib (BIBF 1120)) and changes from baseline to Day 1 at each point in time i.e., 10 time points from 0 to 12 in the PR interval are reported.
Absolute Values at Baseline (Day -1) and Day 15 and Changes From Baseline to Day 15 at Each Point in Time in PR Interval At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 15. Baseline (Day -1) values were taken at exactly the same time points as on Day 15. The PR interval is an electrocardiogram (ECG) interval and is the time from the onset of the P wave to the start of the QRS complex (combination of the Q wave, R wave and S wave). It reflects conduction through the atrioventricular node (AV) node. The normal PR interval is between 120 - 200 milliseconds (ms) (0.12-0.20s) in duration. Absolute values at baseline (Day-1 prior to the first dosing of nintedanib (BIBF 1120) and at Day 15 (steady state) and changes from baseline to Day 15 at each point in time i.e., 10 time points from 0 to 12 in the PR interval are reported.
Absolute Values at Baseline (Day -1) and Day 15 and Changes From Baseline to Day 15 at Each Point in Time in QRS Interval At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 15. Baseline (Day -1) values were taken at exactly the same time points as on Day 15. QRS interval is an electrocardiogram (ECG) interval and is the time interval from the onset to the end of the QRS complex (combination of the Q wave, R wave and S wave). The normal QRS duration is less than 120 milliseconds (ms). Absolute values and changes from baseline (Day-1 prior to the first dosing of nintedanib) to Day 15 (steady state) at each point in time i.e., 10 time points from 0 to 12 in the QRS interval are reported.
Frequency of Patients by Clinical Electrocardiogram (ECG) Measurement Interpretation, Calculated Separately for Days 1 and 15 of Treatment Cycle 1 At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description. Based on the interpretation of the electrocardiogram (ECG) patients were classified in 3 categories:
* Normal (a normal ECG reading would be a reading that includes the following normal findings: 1) normal general features; 2) no arrhythmia; 3) no conduction delays; 4) T-wave morphology of normal; and 5) normal U-wave morphology) on Day 1 or on Day 15)
* Not normal and not normal at baseline (an abnormal ECG reading would be a reading that includes one or more of the following abnormal findings: 1) abnormal general features; 2) arrhythmia; 3) conduction delays; 4) T-wave morphology of flat, inverted or biphasic; and 5) abnormal U-wave morphology) on Day 1 or on Day 15)
* Not normal and new onset of finding; Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.Number of Participants With Adverse Events Requiring or Prolonging Hospitalisation From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months. Number of participants who experienced Adverse Events which required or prolonged hospitalisation of patients is reported for each treatment arm.
Trial Locations
- Locations (15)
Onco.Cent. - Instit. of Maria Sklodowskiej-Curie
🇵🇱Warszawa, Poland
University of Pecs Medical School, Dept. of Oncotherapy
🇭🇺Pecs, Hungary
Ziemia Lubelska Oncological Center, Lublin
🇵🇱Lublin, Poland
Military Central Clinical Emergency Hospital
🇷🇴Bucharest, Romania
ONCOLAB SRL, Craiova
🇷🇴Craiova, Romania
Municipal Establishment Cherkasy Oncology Centre
🇺🇦Cherkasy, Ukraine
Munic.Instit."City Clin.Hosp.#4" of Dnipro City Council
🇺🇦Dnipropetrovks, Ukraine
CI of LRC Lviv Onco.Reg.Treat.&Diag.Cent.
🇺🇦Lviv, Ukraine
Uzhgorod National University, Oncology Centre
🇺🇦Uzhgorod, Ukraine
Sf. Nectarie Oncology Center, Craiova
🇷🇴Craiova, Romania
Bukovynsk State Medical University
🇺🇦Chernivtsi, Ukraine
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, United Kingdom
Surrey Cancer Research Institute
🇬🇧Guildford, United Kingdom
Addenbrooke's Hospital
🇬🇧Cambridge, United Kingdom
St James's University Hospital
🇬🇧Leeds, United Kingdom