E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Uncontrolled bleeding in patients who have taken either a direct factor Xa inhibitor (novel oral anticoagulants) or an indirect factor Xa inhibitor (low molecular weight heparins). |
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E.1.1.1 | Medical condition in easily understood language |
Serious bleeding complications in patients who have taken anticoagulant medicine, known as a factor Xa inhibitor. |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10075279 |
E.1.2 | Term | Anticoagulant reversal therapy |
E.1.2 | System Organ Class | 100000004865 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Two Primary Objectives:
1. To demonstrate the decrease in anti-fXa activity following andexanet treatment.
The study will be considered to have met the first primary efficacy objective if there is a statistically significant (p<0.05) percent decrease in anti-fXa activity from the pre-treatment baseline to the evaluation period nadir (where the evaluation period starts 5 minutes following the end of the andexanet bolus and ends just prior to the end of the andexanet infusion).
2. To evaluate the haemostatic efficacy of andexanet in patients receiving a fXa inhibitor who have acute major bleeding and reduced fXa activity.
The study will be considered to have met the second primary efficacy objective if the proportion of patients with excellent or good haemostasis (as adjudicated by the independent Endpoint Adjudication Committeeis statistically significantly higher than 50% (p<0.05). |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
To assess the relationship between decrease in anti-fXa activity and achievement of haemostatic efficacy in patients receiving a fXa inhibitor who have acute major bleeding and reduced fXa activity.
Exploratory Objectives:
• For patients receiving apixaban, edoxaban or rivaroxaban, to evaluate the decrease in the free fraction of the fXa inhibitor following andexanet treatment.
• To evaluate the use of red blood cell transfusions.
• To evaluate the use of other blood products and haemostatic agents.
• Effect on thrombin generation, level of TFPI, level of ATIII and level of anti-fIIa activity
• Haemostatic efficacy in ICH patients at high risk for haematoma expansion
• Occurrence of re-bleeding
• Change in clinical status for patients with ICH
Safety Objectives:
• To evaluate the overall safety of andexanet, including adjudicated thrombotic events (TEs) and antibodies to fX, fXa, and andexanet
• To evaluate the 30-day all-cause mortality |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Either the patient or his or her medical proxy (or legally acceptable designee) has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening;
2) The patient must be at least 18 years old at the time of Screening;
3) The patient must have an acute overt major bleeding episode requiring urgent reversal of anticoagulation; Acute major bleeding requiring urgent reversal of anticoagulation is defined by at least ONE of the following:
- Acute overt bleeding that is potentially life-threatening, e.g., with signs or symptoms of haemodynamic compromise, such as severe hypotension, poor skin perfusion, mental confusion, low urine output that cannot be otherwise explained;
- Acute overt bleeding associated with a fall in haemoglobin level by ≥ 2 g/dL, OR a Hgb ≤ 8 g/dL if no baseline Hgb is available;
- Acute bleeding in a critical area or organ, such as, intra-spinal, pericardial or intracranial.
4) The patient, for whom the bleeding is intracranial must have undergone a head CT or MRI scan demonstrating the intracranial bleeding. Note: Patients with bleeding at non-intracranial locations do not require a head CT or MRI;
5) The patient received or is believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban or enoxaparin (dose of enoxaparin ≥1mg/kg/d).
6) For patients with ICH, there must be a reasonable expectation that andexanet treatment will commence within 2 hours of the baseline imaging evaluation. |
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E.4 | Principal exclusion criteria |
1) The patient is scheduled to undergo surgery in less than 12 hours with the exception of minimally invasive surgery/procedures (e.g., endoscopy, bronchoscopy, central lines, Burr holes);
2) A patient with ICH has any of the following:
− Glasgow coma score < 7
− Estimated intracerebral haematoma volume >60 cc as assessed by the CT or MRI.
3) Patients with visible, musculoskeletal, or intra-articular bleeding as the qualifying bleed.
4) The patient has an expected survival of less than 1 month;
5) The patient has a recent history (within 2 weeks) of a diagnosed thrombotic event (TE) as follows: venous thromboembolism (VTE; e.g., deep venous thrombosis, pulmonary embolism, cerebral venous thrombosis), myocardial infarction, disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris hospitalization, or severe peripheral vascular disease within 2 weeks prior to Screening;
6) The patient has severe sepsis or septic shock at the time of Screening;
7) The patient is pregnant or a lactating female;
8) The patient has received any of the following drugs or blood products within 7 days or Screening:
• Vitamin K antagonist (VKA) (e.g., warfarin);
• Dabigatran;
• Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or recombinant factor VIIa (rfVIIa) (e.g., NovoSeven®);
• Whole blood, plasma fractions
Note: Administration of platelets or packed red blood cells (PRBCs) is not an exclusion criterion;
9) The patient was treated with an investigational drug <30 days prior to Screening.
10) Planned administration of PCC, fresh frozen plasma (FFP), or rfVIIa from Screening until within 12 hours after the end of the andexanet infusion. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The two primary endpoints are:
1) The percent change from baseline (pre-treatment with andexanet) in anti-fXa activity to the nadir from the evaluation period (where the evaluation period starts 5 minutes following the end of the andexanet bolus and ends 10 minutes after the end of the andexanet infusion).
AND
2) The achievement of haemostatic efficacy.
The primary endpoints, including the evaluation of hemostatic efficacy in specific study populations against specific comparators, will be ordered in a fixed sequence multiple comparisons (i.e., hierarchical) fashion as delineated in the SAP.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients receive andexanet as an IV bolus administered over ~15–30 minutes, followed immediately by a continuous infusion administered over ~120 minutes.
Primary endpoint 1:
Sample for anti-fXa activity is drawn at 2 timepoints; one at (or within 30 minutes after) the end of the bolus, and another at (or within 30 minutes prior to) the end of the infusion.
Primary Endpoint 2:
Haemostatic efficacy: MRI/CT; GCS , mRS and NIHSS for ICH (pre-bolus and at 1hr, 12hr, +7d after end of infusion (EI). Transfusion-corrected haemoglobin and haematocrit for non-visible bleeding (at 12hr); Echocardiogram for pericardial bleed (pre-bolus and at 12hr EI). Ultrasound or CT/MRI scan for intraspinal bleeding (pre-bolus and at 1hr, 12hr, +7d EI). |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints:
The secondary efficacy objective is to assess the relationship between the two primary efficacy endpoints. No additional efficacy endpoint is defined to support the secondary efficacy objective.
Exploratory Endpoints:
• The number of patients receiving one or more red blood cell transfusions from the start of the andexanet bolus through 12 hours after the end of andexanet infusion.
• For patients receiving apixaban, rivaroxaban, or edoxaban, to evaluate the decrease in free fraction of the fXa inhibitor following andexanet administration.
• The number of red blood cell units transfused per patient from the start of the andexanet bolus through 12 hours after the end of the andexanet infusion.
• The use of non-study-prescribed blood products and/or hemostatic agents.
• The occurrence of re-bleeding following andexanet treatment. Re-bleeding is defined as follows: bleeding from the same anatomical site in patients within 24 hours of initial andexanet treatment and after achieving initial good/excellent hemostasis.
• Andexanet reversal of anticoagulant effect as measured through TG parameters (with, endogenous thrombin potential (ETP) as the primary measure), for both the Tissue Factor (TF)-initiated assay and the non-TF-initiated assay.
• TFPI levels, both free and total, pre- and post-administration of andexanet.
• ATIII levels, pre- and post-administration of andexanet.
• Anti-factor IIa levels, pre- and post-administration of andexanet (enoxaparin patients only).
• The achievement of hemostatic efficacy in ICH patients at high risk of hematoma expansion.
• Change from baseline in GCS (for ICH patients only).
• Change from baseline in mRS (for ICH patients only).
• Change from baseline in NIHSS (for ICH patients only).
Safety Measurements:
-Survival status, AEs, vital signs, and clinical laboratory measurements
-Centrally-adjudicated Treatment-Emergent Adverse Events
-Antibodies to andexanet, fX, and fXa. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Exploratory:
-No. of red blood cell units transfused, use of non-study-prescribed hemostatic agents (start of bolus through 12 hr)
-Free fraction of the direct fXa inhibitor (pre-bolus and 4hr, 8hr 12hr)
-Re-bleeding within 24 hours
-TG parameters (with ETP as primary measure), for both the TF-initiated and non-TF-initiated assay (pre-bolus, end of bolus, end of infusion, 4hr, 8hr 12hr 24, 48, 72hr, +7days)
-ATIII and TFPI levels, pre- and post-administration of andexanet (-30 min EI, 4hr, 8hr 12hr 24, 48, 72hr, +7days)
-Anti-factor IIa levels, pre- and post-administration
-GCS, mRS and NIHSS (pre-bolus and at 1 hr, 12 hrs, and 30 days (for ICH only)).
Safety:
Antibodies to andexanet, fX, and fXa (pre-bolus and +7 days)
AEs (followed through Study Day 30 post-treatment visit. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
France |
Germany |
Japan |
Netherlands |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |