Hemorrhage
Conditions
Brief summary
The trial objective is to demonstrate the safety of idarucizumab, as assessed by the occurence of patients with drug related adverse events (including immune reactions) and all-cause mortality in paediatric venous thromboembolism 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 effect of dabigatran is needed.
Interventions
DRUGIdarucizumab
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
Patients taking dabigatran etexilate in the paediatric trials 1160.106 or 1160.108 are eligible for this trial if they meet the following criteria: Group A: * Overt bleeding judged by the treating physician to require a reversal agent. * Currently taking dabigatran etexilate in the context of a clinical trial with dabigatran etexilate (1160.106 or 1160.108). * Male or female patients from 0 to less than 18 years of age at the time of informed consent/assent for participation in trial 1160.106 or in trial 1160.108. * Female patients of childbearing potential (defined as having experienced menarche) must have followed the contraception requirements according to the dabigatran trial 1160.106 or trial 1160.108 in which they are enrolled. * Written informed consent provided by the patient (and/or the patient's legally accepted representative) and assent provided by the patient (if applicable) at the time of informed consent signature in accordance with Good Clinical Practice (GCP) and local legislation prior to admission to the trial. If the child is unable to give assent at the time of the emergency, the assent, when applicable will be obtained as soon as feasible. Group B: * A condition requiring an emergency surgery or invasive procedure where adequate haemostasis is required. Emergency is defined as need for surgery or intervention within the following 8 hours. * Currently taking dabigatran etexilate in the context of a clinical trial with dabigatran etexilate (1160.106 or 1160.108). * Male or female patients from 0 to less than 18 years of age at the time of informed consent/assent for participation in trial 1160.106 or in trial 1160.108. * Female patients of childbearing potential (defined as having experienced menarche) must have followed the contraception requirements according to the dabigatran trial 1160.106 or trial 1160.108 in which they are enrolled. * Written informed consent provided by the patient (and/or the patient's legally accepted representative) and assent provided by the patient (if applicable) at the time of informed consent signature in accordance with GCP and local legislation prior to admission to the trial. If the child is unable to give assent at the time of the emergency, the assent, when applicable will be obtained as soon as feasible.
Exclusion criteria
Group A: * Patients with minor bleeding (e.g. epistaxis, haematuria) who can be managed with standard supportive care. * Patients with no clinical signs of bleeding. * Patients with body weight \< 2.5 kg * Contraindications to trial medication including known hypersensitivity to the drug or its excipients; i.e. patients with hereditary fructose intolerance who may react to sorbitol. * Female patients who are pregnant, nursing, or who plan to become pregnant while in the trial. Group B: * A surgery or procedure which is elective or where the risk of uncontrolled or unmanageable bleeding is low. * Patients with body weight \< 2.5 kg * Contraindications to trial medication including known hypersensitivity to the drug or its excipients; i.e. patients with hereditary fructose intolerance who may react to sorbitol. * Female patients who are pregnant, nursing, or who plan to become pregnant while in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Drug-related Adverse Events (AEs) | From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days | Number of participants with drug-related adverse events (AEs) including immune reactions and all cause mortality during the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Achieve Reversal of the Dabigatran Effect (Based on the Coagulation Time for dTT and ECT) | From end of vial 2 of Idarucizumab up to 24h. | 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 (h). Reversal of the dabigatran effect at time t was defined as the 100 percent (%) \*(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. |
| Duration of Reversal of the Dabigatran Effect Sustained up to 24 Hours Post-dose (Based on the Coagulation Time for dTT and ECT) | From end of vial 2 of Idarucizumab up to 24h. | 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. |
| Number of Participants With Cessation of Bleeding | From vial 1 of Idarucizumab through vial 2 of Idarucizumab, up to 24h 30min. | — |
| Percent Change of Coagulation Time for Diluted Thrombin Time (dTT) and Ecarin Clotting Time (ECT) at 30 Minutes Post-dose Compared With Pre-dose | At immediately prior to administration of vial 1 of Idarucizumab and 30 minutes (min) post vial 2 administration. | 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. |
| Number of Participants With Clinical Conditions Contributing to Bleeding During the Trial | From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days | Number of participants with clinical conditions (trauma, surgery and use of antiplatelet) contributing to bleeding during the trial were characterized. |
| Number of Participants Developing Treatment-emergent Antidrug Antibodies (ADA) With Cross Reactivity to Idarucizumab | At day 25 post vial 2 of Idarucizumab administration, up to 1 day | — |
| Number of Participants Per Bleeding Status During the Trial | From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days | Numbers of participants whose bleeding had stopped, reduced, unchanged, worsened or not applicable during the trial were characterized. |
Countries
Russia
Participant flow
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 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.
Participants by arm
| Arm | Count |
|---|---|
| Idarucizumab 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. | 1 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Prematurely discontinued of the trial | 1 |
Baseline characteristics
| Characteristic | Idarucizumab |
|---|---|
| Age, Continuous | NA Years |
| Race/Ethnicity, Customized | NA Participants |
| Sex: Female, Male Female | NA Participants |
| Sex: Female, Male Male | NA Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Number of Participants With Drug-related Adverse Events (AEs)
Number of participants with drug-related adverse events (AEs) including immune reactions and all cause mortality during the trial.
Time frame: From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days
Population: 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idarucizumab | Number of Participants With Drug-related Adverse Events (AEs) | 0 Participants |
Secondary
Duration of Reversal of the Dabigatran Effect Sustained up to 24 Hours Post-dose (Based on the Coagulation Time for dTT and ECT)
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.
Time frame: From end of vial 2 of Idarucizumab up to 24h.
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idarucizumab | Duration of Reversal of the Dabigatran Effect Sustained up to 24 Hours Post-dose (Based on the Coagulation Time for dTT and ECT) | 23.5 Hours |
Secondary
Number of Participants Developing Treatment-emergent Antidrug Antibodies (ADA) With Cross Reactivity to Idarucizumab
Time frame: At day 25 post vial 2 of Idarucizumab administration, up to 1 day
Population: 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, as well as ADA.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idarucizumab | Number of Participants Developing Treatment-emergent Antidrug Antibodies (ADA) With Cross Reactivity to Idarucizumab | 0 Participants |
Secondary
Number of Participants Per Bleeding Status During the Trial
Numbers of participants whose bleeding had stopped, reduced, unchanged, worsened or not applicable during the trial were characterized.
Time frame: From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days
Population: 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, as well as ADA.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idarucizumab | Number of Participants Per Bleeding Status During the Trial | Stopped | 1 Participants |
| Idarucizumab | Number of Participants Per Bleeding Status During the Trial | Reduced | 0 Participants |
| Idarucizumab | Number of Participants Per Bleeding Status During the Trial | Unchanged | 0 Participants |
| Idarucizumab | Number of Participants Per Bleeding Status During the Trial | Worsened | 0 Participants |
| Idarucizumab | Number of Participants Per Bleeding Status During the Trial | Not applicable | 0 Participants |
Secondary
Number of Participants With Cessation of Bleeding
Time frame: From vial 1 of Idarucizumab through vial 2 of Idarucizumab, up to 24h 30min.
Population: 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, as well as ADA.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Idarucizumab | Number of Participants With Cessation of Bleeding | 1 Participants |
Secondary
Number of Participants With Clinical Conditions Contributing to Bleeding During the Trial
Number of participants with clinical conditions (trauma, surgery and use of antiplatelet) contributing to bleeding during the trial were characterized.
Time frame: From vial 1 of Idarucizumab until prematurely discontinued of the trial, up to 25 days
Population: 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, as well as ADA.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Idarucizumab | Number of Participants With Clinical Conditions Contributing to Bleeding During the Trial | Trauma | 1 Participants |
| Idarucizumab | Number of Participants With Clinical Conditions Contributing to Bleeding During the Trial | Surgery | 0 Participants |
| Idarucizumab | Number of Participants With Clinical Conditions Contributing to Bleeding During the Trial | Use of antiplatelet | 0 Participants |
Secondary
Percent Change of Coagulation Time for Diluted Thrombin Time (dTT) and Ecarin Clotting Time (ECT) at 30 Minutes Post-dose Compared With Pre-dose
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.
Time frame: At immediately prior to administration of vial 1 of Idarucizumab and 30 minutes (min) post vial 2 administration.
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Idarucizumab | Percent Change of Coagulation Time for Diluted Thrombin Time (dTT) and Ecarin Clotting Time (ECT) at 30 Minutes Post-dose Compared With Pre-dose | Diluted thrombin time (dTT) | -46.3 Percentage of time in seconds |
| Idarucizumab | Percent Change of Coagulation Time for Diluted Thrombin Time (dTT) and Ecarin Clotting Time (ECT) at 30 Minutes Post-dose Compared With Pre-dose | Ecarin clotting time (ECT) | -67.8 Percentage of time in seconds |
Secondary
Time to Achieve Reversal of the Dabigatran Effect (Based on the Coagulation Time for dTT and ECT)
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 (h). Reversal of the dabigatran effect at time t was defined as the 100 percent (%) \*(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.
Time frame: From end of vial 2 of Idarucizumab up to 24h.
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idarucizumab | Time to Achieve Reversal of the Dabigatran Effect (Based on the Coagulation Time for dTT and ECT) | 30 Minutes |