E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Uncontrolled Major or Life Threatening Bleeding or Requiring Urgent Surgery or Invasive Procedure |
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E.1.1.1 | Medical condition in easily understood language |
Uncontrolled Major or Life Threatening Bleeding or Requiring Urgent Surgery or Invasive Procedure |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053756 |
E.1.2 | Term | Invasive procedure |
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 |
• To demonstrate reversal of the antiplatelet effects of ticagrelor after initiation of the intravenous (IV) infusion of PB2452 using the VerifyNow™ PRUTest™ (VerifyNow™, 2016) platelet function assay in ticagrelor-treated patients presenting with uncontrolled major or life-threatening bleeding or requiring urgent surgery or invasive procedure • To demonstrate the effect of PB2452 on achievement of effective hemostasis after administration of PB2452 in ticagrelor-treated patients presenting with uncontrolled major or life-threatening bleeding or requiring urgent surgery or invasive procedure |
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E.2.2 | Secondary objectives of the trial |
• To demonstrate reversal of the antiplatelet effects of ticagrelor with intravenous (IV) infusion of PB2452 by measurement of the platelet reactivity index (PRI) using the vasodilator-stimulated phosphoprotein (VASP) assay in addition to PRU in ticagrelor-treated patients presenting with uncontrolled major or life-threatening bleeding or requiring urgent surgery or invasive procedure |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female > 18 years of age with documented or verbal informed consent. Emergency consent may be obtained where permitted by local regulations and institutional approval 2. History or documentation of ticagrelor intake within the prior 3 days 3. Patients described below who require urgent reversal of the antiplatelet effects of ticagrelor: Patients with uncontrolled major or life-threatening bleeding, requiring urgent reversal of the antiplatelet effects of ticagrelor. It is expected that enrolled patients would have characteristics similar to those described below: • Potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise, e.g., systolic blood pressure < 90 mm Hg and signs or symptoms of low cardiac output not otherwise explained • Bleeding in a critical organ or closed space, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular bleed with compartment syndrome • Visible, uncontrolled bleeding associated with a corrected hemoglobin level < 8.0 g/dL, a fall in hemoglobin level of ≥ 2.0 g/dL (1.24 mmol/L) from a known baseline, or requirement for transfusion of 2 or more units of packed red blood cells (PRBC) Patients requiring urgent surgery or invasive procedure when it is not medically advisable either to proceed urgently with impaired hemostasis or to delay the urgent procedure for 3 or more days due to the high risk of bleeding. These patients may typically be in any of the following clinical situations: • Requires urgent surgery or invasive procedure known to be associated with a risk of significant bleeding (such as cardiac surgery, neurosurgery, or major orthopedic surgery) • Requires urgent surgery or invasive procedure that may have an adverse procedural outcome if hemostasis is impaired (such as neurological, spinal, ophthalmological, urological, or orthopedic surgery) • At risk of experiencing life-threatening events, such as, shock, myocardial infarction, or stroke, if significant intraoperative or postoperative bleeding occurs (such as in elderly patients or patients with underlying cardiac or pulmonary disease who have limited cardiopulmonary reserve) |
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E.4 | Principal exclusion criteria |
1. Known sensitivity or contraindication to PB2452 or any of its excipients 2. Patients in whom ticagrelor reversal is not considered urgent, e.g., patients with stable or non-acute conditions who have low hemoglobin due to chronic, low-grade gastrointestinal bleeding or who have stable, remote, or asymptomatic intracranial hemorrhage 3. Patients expected to be clinically unsalvageable, such as, patients with end-stage cancer or patients with overwhelming sepsis 4. Any condition which, in the opinion of the investigator, would make it unsafe or unsuitable for the patients to participate in this study. This includes assessment of likelihood to cooperate with study follow-up visits and procedures Known pregnancy may be exclusionary in some regions or countries as directed by national health authorities and/or local IRBs/Ethics Committees 5. Known use of clopidogrel, prasugrel, or ticlopidine within 5 days of study drug administration; known use of antiplatelet GPIIb/IIIa inhibitors, or cangrelor within 5 half-lives of study drug administration; or known use of warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban within 5 half-lives of expected study drug administration 6. Known recent use (< 5 day) of vitamin K, prothrombin complex concentrate, recombinant factor VIIa, idarucizumab, or andexanet-alfa (coagulation factor Xa (recombinant), inactivated-zhzo). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary reversal endpoint: The minimum % inhibition of PRU within 4 hours of the initiation of study drug as assessed by the VerifyNow™ PRUTest™ platelet function assay. Percent inhibition of PRU is calculated as 100 * [(180 – PRUtrt)/180]. PRUtrt refers to the PRU value measured posttreatment with the study drug. PRU of 180 is considered the lower limit of normal (LLN) platelet function as described in the VerifyNow™ PRUTest™ manufacturer’s user guidance
Primary hemostasis endpoint: Achievement of effective hemostasis after initiation of PB2452 infusion will be assessed in each population separately and then pooled for primary endpoint analysis. In patients with uncontrolled major bleeding, achievement of effective hemostasis will be assessed using prespecified criteria for effective hemostasis for visible and non-visible major bleeding adapted from (Connolly, 2016). In patients undergoing urgent surgery or invasive procedure, achievement of effective hemostasis following initiation of PB2452 infusion will be centrally adjudicated using prespecified criteria for effective hemostasis derived from the GUSTO clinical bleeding scale (GUSTO, 1993). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to Appendix 3:schedule of events |
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E.5.2 | Secondary end point(s) |
• Minimum % inhibition of PRI assessed by VASP within 4 hours after the initiation of study drug. Percent inhibition of PRI is calculated as 100 * [(PRIbsl – PRItrt)/ PRIbsl]. PRItrt refers to the PRI value measured posttreatment with the study drug. PRIbsl is the lower limit of normal obtained from previous studies in healthy volunteers • Maximum reversal of PRU assessed by VerifyNow™ PRUTest™ within 4 hours after the initiation of study drug. Percent reversal is calculated as 100 * [(PRUtrt – PRUpre-trt)/(180– PRUpre-trt)]. PRUpre-trt is defined as the PRU value prior to administration of study drug. PRU of 180 is considered as the lower limit of normal (LLN) for platelet function as described in the VerifyNow™ PRUTest™ package insert • Maximum reversal of PRI assessed by VASP within 4 hours after the initiation of study drug. Percent reversal is calculated as 100 * [(PRItrt – PRIpre-trt)/(LLN – PRIpre-trt)]. PRIpre-trt is defined as the PRU value prior to administration of study drug. LLN of PRI is obtained from previous studies in healthy volunteers • Proportion of subjects achieving 60%, 80% or 100% reversal of platelet inhibition by ticagrelor using PRU and PRI at any time point during the treatment period • Duration of at least 60%, 80%, and 100% reversal by PRU and PRI |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to Appendix 3:schedule of events |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 |
Canada |
China |
United States |
Switzerland |
Austria |
Belgium |
France |
Germany |
Italy |
Netherlands |
Spain |
Sweden |
United Kingdom |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 11 |
E.8.9.2 | In all countries concerned by the trial years | 2 |