Clinical Trial Results:
Single dose, open label, uncontrolled, safety trial of intravenous administration of idarucizumab to paediatric patients enrolled from ongoing phase IIb/III clinical trials with dabigatran etexilate for the treatment and secondary prevention of venous thromboembolism.
|
Summary
|
|
EudraCT number |
2015-002177-37 |
Trial protocol |
SE LT CZ IT DE Outside EU/EEA GR HU BE ES BG AT FI FR |
Global end of trial date |
19 Oct 2019
|
|
Results information
|
|
Results version number |
v2(current) |
This version publication date |
24 Dec 2020
|
First version publication date |
16 Apr 2020
|
Other versions |
v1 |
Version creation reason |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
1321.7
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02815670 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Boehringer Ingelheim
|
||
Sponsor organisation address |
Binger Strasse 173, Ingelheim am Rheim, Germany, 55216
|
||
Public contact |
Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
|
||
Scientific contact |
Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
|
||
EMA paediatric investigation plan number(s) |
EMEA-001438-PIP01-13 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
18 Dec 2019
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
19 Oct 2019
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
19 Oct 2019
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
To demonstrate the safety of idarucizumab, as assessed by the occurrence of patients with drug related adverse events (including immune reactions) and all-cause mortality in paediatric venous thromboembolism (VTE) patients treated with dabigatran in ongoing clinical trials who require emergency surgery/urgent procedures or patients who have life-threatening or uncontrolled bleeding which requires urgent intervention, when rapid reversal of the anticoagulant effects of dabigatran is needed.
|
||
Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required. The number 1 for age category 'In Utero' in trial population does not reflect the true age of this participant. The age information is not provide for protection of pediatric participant.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Mar 2017
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Russian Federation: 1
|
||
Worldwide total number of subjects |
1
|
||
EEA total number of subjects |
0
|
||
Number of subjects enrolled per age group |
|||
In utero |
1
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||
|
Recruitment
|
|||||||||||
Recruitment details |
An open-label, uncontrolled case series trial, with a single treatment arm of idarucizumab in patients with venous thromboembolism treated with dabigatran etexilate in ongoing Boehringer Ingelheim pediatric clinical trials (1160.106 and 1160.108). Treatment period was around 1 day followed by 29 days of safety follow-up period. | ||||||||||
|
Pre-assignment
|
|||||||||||
Screening details |
All subjects were screened for eligibility to participants in the trial. Subjects attended specialist sites which would then ensure that they met all strictly implemented inclusion/exclusion criteria. Subjects were not to be assigned to treatment groups if any one of the specific entry criteria were violated. | ||||||||||
|
Period 1
|
|||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||
Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Non-randomised - controlled
|
||||||||||
Blinding used |
Not blinded | ||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
Idarucizumab | ||||||||||
Arm description |
2.5 gram (g) per 50 milliliter (mL) vial of Idarucizuma was administrated via intravenous injection (vial 1) with (in order of preference): a 5 minutes (min) infusion with an infusion pump, a 10 to 15 min drip, or intravenous push with a syringe followed by another injection (vial 2) of same dosage of Idarucizumab for participants who were treated with dabigatran and had uncontrolled or life threatening bleeding that required urgent medical or surgical intervention or who required emergency surgery/urgent procedures where adequate haemostasis was required (total dosage: up to 5g based on the weight of participant). Two equal injection parts were administered no more than 15 min apart. The time between start of injection of the first vial and end of the second vial was 22 min followed by 24 hours post-dose observation period. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Idarucizumab
|
||||||||||
Investigational medicinal product code |
|||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Solution for injection/infusion
|
||||||||||
Routes of administration |
Intravenous use
|
||||||||||
Dosage and administration details |
2 injections of 2.5 gram (g) per 50 milliliter (mL) vial of Idarucizuma (total: up to 5g based on the weight of participant) were administrated via intravenous injection (vial 1) followed by another injection (vial 2) of same dosage of Idarucizumab for participants who were treated with dabigatran and had uncontrolled or life threatening bleeding that required urgent medical or surgical intervention or who required emergency surgery/urgent procedures where adequate haemostasis was required. Two equal injection parts were administered no more than 15 minutes (min) apart. The time between start of injection of the first vial and end of the second vial was 22 min.
|
||||||||||
|
|||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Idarucizumab
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
2.5 gram (g) per 50 milliliter (mL) vial of Idarucizuma was administrated via intravenous injection (vial 1) with (in order of preference): a 5 minutes (min) infusion with an infusion pump, a 10 to 15 min drip, or intravenous push with a syringe followed by another injection (vial 2) of same dosage of Idarucizumab for participants who were treated with dabigatran and had uncontrolled or life threatening bleeding that required urgent medical or surgical intervention or who required emergency surgery/urgent procedures where adequate haemostasis was required (total dosage: up to 5g based on the weight of participant). Two equal injection parts were administered no more than 15 min apart. The time between start of injection of the first vial and end of the second vial was 22 min followed by 24 hours post-dose observation period. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Idarucizumab
|
||
Reporting group description |
2.5 gram (g) per 50 milliliter (mL) vial of Idarucizuma was administrated via intravenous injection (vial 1) with (in order of preference): a 5 minutes (min) infusion with an infusion pump, a 10 to 15 min drip, or intravenous push with a syringe followed by another injection (vial 2) of same dosage of Idarucizumab for participants who were treated with dabigatran and had uncontrolled or life threatening bleeding that required urgent medical or surgical intervention or who required emergency surgery/urgent procedures where adequate haemostasis was required (total dosage: up to 5g based on the weight of participant). Two equal injection parts were administered no more than 15 min apart. The time between start of injection of the first vial and end of the second vial was 22 min followed by 24 hours post-dose observation period. | ||
|
|||||||
End point title |
Number of participants with drug-related adverse events (AEs) [1] | ||||||
End point description |
Number of participants with drug-related adverse events (AEs) including immune reactions and all cause mortality during the trial. Treated set (TS): including all patients who received any dose of Idarucizumab. The TS was used to assess safety, clinical endpoints, demographics and baseline characteristics, concomitant diagnosis/therapy and medical history, and antidrug antibodies (ADA).
|
||||||
End point type |
Primary
|
||||||
End point timeframe |
From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days
|
||||||
| 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: This endpoint was evaluated only descriptively. Thus, no statistical analysis was performed. |
|||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||
End point title |
Percent change of coagulation time for diluted thrombin time (dTT) and ecarin clotting time (ECT) at 30 minutes post-dose compared with pre-dose | ||||||||||||
End point description |
Percent change of coagulation time for diluted thrombin time (dTT) and ecarin clotting time (ECT) at 30 minutes (min) post-dose compared with pre-dose. Central blood sampling for dTT, ECT were to occur immediately prior to administration of each vial of Idarucizumab and post-dose at 30min, 4h, 12h and 24h. Pharmacodynamic (PD) set (PDS): comprising all patients in the TS who provided at least 1 evaluable pre-dose and at least 1 post-dose observation for PD endpoints or biomarker measures. The PDS was used for the PD endpoint analyses. Note that for different PD endpoints or biomarkers, the number of evaluable patients could differ between endpoints.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
At immediately prior to administration of vial 1 of Idarucizumab and 30 minutes (min) post vial 2 administration.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||
End point title |
Time to achieve reversal of the dabigatran effect (based on the coagulation time for dTT and ECT) | ||||||
End point description |
Idarucizumab administration resulted in normalisation of dTT and ECT. Time to achieve reversal of anticoagulant effect of dabigatran based on the coagulation time for dTT and ECT, at any time point from the end of the second injection (vial 2) up to 24 hours . Reversal of the dabigatran effect at time t was defined as the 100 % *(pre-dose coagulation time - post-dose coagulation time at time t)/(pre-dose coagulation test - upper limit of normal). Values equal to or higher than 100% were interpreted as reversal. Central blood sampling for dTT, ECT were to occur immediately prior to administration of each vial of Idarucizumab and post-dose at 30min, 4h, 12h and 24h. PD set : comprising all patients in the TS who provided at least 1 evaluable pre-dose and at least 1 post-dose observation for PD endpoints or biomarker measures. The PDS was used for the PD endpoint analyses. Note that for different PD endpoints, the number of evaluable patients could differ between endpoints.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
From end of vial 2 of Idarucizumab up to 24h.
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
Duration of reversal of the dabigatran effect sustained at 24 hours post-dose (based on the coagulation time for dTT and ECT) | ||||||||
End point description |
Duration of reversal, defined as the time period a patient remained completely reversed based on dTT and ECT, up to 24 hours post-dose or restarting the treatment of anticoagulation. Central blood sampling for dTT, ECT were to occur immediately prior to administration of each vial of idarucizumab and post-dose at 30min, 4h, 12h and 24h. Pharmacodynamic (PD) set (PDS): comprising all patients in the TS who provided at least 1 evaluable pre-dose and at least 1 post-dose observation for PD endpoints or biomarker measures. The PDS was used for the PD endpoint analyses. Note that for different PD endpoints or biomarkers, the number of evaluable patients could differ between endpoints.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From end of vial 2 of Idarucizumab up to 24h.
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||
End point title |
Number of participants with cessation of bleeding | ||||||
End point description |
Treated set (TS): including all patients who received any dose of Idarucizumab. The TS was used to assess safety, clinical endpoints, demographics and baseline characteristics, concomitant diagnosis/therapy and medical history, and antidrug antibodies (ADA).
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
From vial 1 of Idarucizumab through vial 2 of Idarucizumab, up to 24h 30min.
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||||||
End point title |
Number of participants per bleeding status during the trial | ||||||||||||||||
End point description |
Numbers of participants whose bleeding had stopped, reduced, unchanged, worsened or not applicable during the trial were characterized. Treated set (TS): including all patients who received any dose of Idarucizumab. The TS was used to assess safety, clinical endpoints, demographics and baseline characteristics, concomitant diagnosis/therapy and medical history, and antidrug antibodies (ADA).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Number of participants with clinical conditions contributing to bleeding during the trial | ||||||||||||
End point description |
Number of participants with clinical conditions (trauma, surgery and use of antiplatelet) contributing to bleeding during the trial were characterized. Treated set (TS): including all patients who received any dose of Idarucizumab. The TS was used to assess safety, clinical endpoints, demographics and baseline characteristics, concomitant diagnosis/therapy and medical history, and antidrug antibodies (ADA).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||
End point title |
Number of participants developing treatment-emergent antidrug antibodies (ADA) with cross reactivity to Idarucizumab | ||||||
End point description |
Treated set (TS): including all patients who received any dose of Idarucizumab. The TS was used to assess safety, clinical endpoints, demographics and baseline characteristics, concomitant diagnosis/therapy and medical history, and antidrug antibodies (ADA).
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
At day 25 post vial 2 of Idarucizumab administration, up to 1 day
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||||
|
Adverse events information
|
|||||||||||||||
Timeframe for reporting adverse events |
From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days
|
||||||||||||||
Adverse event reporting additional description |
Treated set (TS): including all patients who received any dose of Idarucizumab. The TS was used to assess safety, clinical endpoints, demographics and baseline characteristics, concomitant diagnosis/therapy and medical history, and antidrug antibodies (ADA).
|
||||||||||||||
Assessment type |
Systematic | ||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||
Dictionary version |
22.1
|
||||||||||||||
|
Reporting groups
|
|||||||||||||||
Reporting group title |
Idarucizumab
|
||||||||||||||
Reporting group description |
2.5 gram (g) per 50 milliliter (mL) vial of Idarucizuma was administrated via intravenous injection (vial 1) with (in order of preference): a 5 minutes (min) infusion with an infusion pump, a 10 to 15 min drip, or intravenous push with a syringe followed by another injection (vial 2) of same dosage of Idarucizumab for participants who were treated with dabigatran and had uncontrolled or life threatening bleeding that required urgent medical or surgical intervention or who required emergency surgery/urgent procedures where adequate haemostasis was required (total dosage: up to 5g based on the weight of participant). Two equal injection parts were administered no more than 15 min apart. The time between start of injection of the first vial and end of the second vial was 22 min. | ||||||||||||||
|
|||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||
|
|||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The patient had completed the treatment period, but the end-of-trial visit was by mistake scheduled 5 days earlier. Thus, the patient was formally considered as having prematurely discontinued the trial although all planned visits were performed. | |||
