This study has been transitioned to CTIS with ID 2022-503012-16-00 check the CTIS register for the current data. To evaluate intraoperative efficacy of PROTHROMPLEX TOTAL in comparison with standard of care (SOC) 4F-PCC, for reversal of…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Urgent Surgery/Invasive Procedure
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint of this study is the occurrence of intraoperative
effective hemostasis assessed at the end of the surgery/invasive procedure
based on the surgeon's assessment using the Four Point Intraoperative
Hemostatic Efficacy Scale. At the IA and FA timepoints, the respective
one-sided significance level α1*and α2* corresponding to the efficacy crossing
boundaries will be calculated, and the primary endpoint will be analyzed as a
dichotomous variable as effective or non-effective hemostasis in a
noninferiority design. The proportion of subjects achieving intraoperative
effective hemostasis will be calculated. Noninferiority will be declared if the
lower confidence limit of a two-sided 100*(1-2 αi*)% confidence interval (CI)
(i=1 for IA and i=2 for FA) for the difference (between PROTHROMPLEX TOTAL and
active comparator 4F-PCC) in the proportion of subjects in both the
Per-Protocol (PP) Set and the mITT Set, respectively, who experience
intraoperative effective hemostasis at the end of surgery is greater than a
noninferiority margin of -12%. Superiority will be tested only in the mITT Set
following a successful test of noninferiority in this set, based on whether the
lower limit of the
2-sided 100*(1- 2 αi*)% CI is >0. The CI for the difference in proportion will
be calculated by the Wilson score method with continuity correction. The
testing for superiority will be exploratory.
Given that the half-life of Factor Xa inhibitors ranges between 5 to 15 hours
and based on the fact that anti-Factor Xa levels remain above the recommended
threshold for reversal for urgent surgery in all subjects within 15 hours of
last Factor Xa inhibitor use, the placebo response rate could be expected to be
around 0% within the prerequisite 15-hour study window. Thus, the estimates of
the success rates for the 4F-PCC in the 8 studies could be considered as their
effect sizes versus placebo (M1). Calculations of the noninferiority margin
(M2) have been performed using the fixed margin method and the point estimate
method for various scenarios of the fraction of the SOC effect that is assumed
to be retained by PROTHROMPLEX TOTAL. There is no clearly established threshold
for clinically meaningful difference. Based on clinical judgement, preserving
more than 85% of the putative SOC-placebo difference would be an adequately
conservative choice. A difference of 12% in the proportion corresponds to the
preservation of 85% of the effect and is thus chosen. In an area with limited
data, with the 8 studies in the meta-analysis reflecting all that was
identified in a systematic literature review approach, Takeda felt appropriate
in choosing the margin based on the meta-analysis results.
Secondary outcome
The analyses of the dichotomous secondary efficacy endpoints of occurrence of
postoperative effective hemostasis assessed at 24 hours after the end of
investigational product infusion (PROTHROMPLEX TOTAL or comparator 4F-PCC)
based on the surgeon's assessment using the Four Point Postoperative Hemostatic
Efficacy Scale, occurrence of intraoperative effective hemostasis assessed at
the end of the surgery/invasive procedure based on the surgeon*s assessment
using the Hemostatic Efficacy Rating Algorithm, usage of blood products or
non-study hemostatic agents for bleeding control within 24 hours after the end
of investigational product infusion, will be analyzed as dichotomous variables
in a noninferiority design as the primary endpoint. The CI for the difference
in proportion for each of these secondary endpoints will be calculated by the
Wilson score method with continuity correction. For each of these secondary
endpoints, noninferiority will be declared if the lower limit of the CI for the
difference in proportions is greater than the noninferiority margin of -12%.
Superiority will be based on whether the lower limit of the CI is >0. The
testing for superiority will be exploratory. The non-dichotomous secondary
efficacy endpoint of number of units of PRBCs administered to achieve bleeding
control within 24 hours after the end of investigational product infusion will
be analyzed using a negative binomial distribution allowing for different shape
parameters per treatment arm via SAS PROC GLIMMIX. The CI for the ratio in the
number of units per subject per 24 hours of PROTHROMPLEX TOTAL relative to the
active comparator 4F-PCC will be reported.
The analyses of the secondary efficacy endpoints at the IA and FA timepoints
will follow a graphical testing approach. This approach for multiple
comparisons will be used to control the type I error (1-sided alpha of 0.025)
for the testing of the secondary efficacy endpoints. The approach is based on a
sequentially rejective Bonferroni multiple-testing procedure to control the
family-wise error rate.
Background summary
The use of Factor Xa inhibitors has dramatically increased since their
introduction in 2010, due to several advantages compared to Vitamin K
antagonists, including rapid onset of action and elimination, predictable
pharmacokinetics, improved safety profile, and reduced food-drug and drug-drug
interactions. However, similar to other anticoagulants, patients using Factor
Xa inhibitors are at increased risk of developing major bleeding, and or may
suffer from a medical emergency requiring urgent surgery. While published
reports suggest interruption of Factor Xa inhibitor therapy for 1 or 2 days
depending on the perioperative bleeding risk prior to elective surgery,
temporary interruption is not a viable option in patients needing for an urgent
intervention associated with a high risk of bleeding.
To date there is no approved drug for reversal of Factor Xa inhibitors for
urgent surgery. Clinical practice for Factor Xa inhibitor reversal for urgent
surgery is highly variable. Published guidelines and guidance reports recommend
the use of prothrombin complex concentrates
(PCCs) for Factor Xa inhibitor reversal when a Factor Xa inhibitor specific
reversal agent is not available.
Study objective
This study has been transitioned to CTIS with ID 2022-503012-16-00 check the CTIS register for the current data.
To evaluate intraoperative efficacy of PROTHROMPLEX TOTAL in comparison with
standard of care (SOC) 4F-PCC, for reversal of anticoagulation in patients
receiving direct oral Factor Xa inhibitors and requiring urgent
surgery/invasive procedure within 15 hours from the last dose of Factor Xa
inhibitor or at any time after that if their specific DOAC-calibrated
(apixaban, rivaroxaban or edoxaban) anti-FXa levels were > 75ng/mL or
heparin-calibrated anti FXa assay level of >0.5 IU/mL at screening.
Study design
This is a Phase 3, multicenter, open-label, adaptive group sequential
noninferiority study to evaluate the efficacy and safety of PROTHROMPLEX TOTAL
in comparison with SOC
4F-PCC for reversal of anticoagulation in patients receiving direct oral Factor
Xa inhibitors and requiring urgent surgery/invasive procedure within 15 hours
from the last dose of Factor Xa inhibitor.
The study is designed to establish non-inferiority of PROTHROMPLEX TOTAL as
compared to investigator-assigned 4F-PCC as a part of SOC, in terms of
intraoperative effective hemostasis based on the surgeon's assessment at the
end of the surgery/invasive procedure. Subjects will be typically identified in
the emergency department or surgical care units of participating hospitals.
Determination of whether the patient is being treated with direct oral Factor
Xa inhibitors
(eg, apixaban, edoxaban, or rivaroxaban) will be based on information provided
by the patient, a patient representative (family member/relative), or the
patient*s physician. Initial assessment of the patient will be performed on
presentation to a treating facility to confirm the subject*s eligibility for
the trial. After a subject is initially considered qualified, informed consent
will be obtained. Subjects will be excluded if the time of the last dose of
Factor Xa is unknown.
Intervention
Patients will be randomly (like pulling a name from a hat) assigned to receive
either the study drug or comparator drug. The chance that the patients will
receive the study drug is 1 in 2 patients.
The study drug or comparator drug will be given to patients one time within 1
hour before their scheduled surgery or medical procedure in the form of a drip
in a vein in their arm. This is called an intravenous (IV) infusion.
This is an open-label study. The pharmacist, and the doctor who will be giving
patients anaesthesia (medicine to numb them or put them to sleep during the
surgery) will know which study treatment they are receiving. However, their
surgeon will not know which study treatment they are receiving before or during
their surgery. They may receive a second dose of the study drug during the
surgery, if needed.
Within 1 hour after the surgery is completed, a few tests will be done to check
if the study treatment is working.
Study burden and risks
The PROTHROMPLEX TOTAL may help in prevention of bleeding, but this is not
certain.
Patients could experience an allergic reaction with the use of study drug or
other medicines to treat their condition. Allergic reactions are serious and
could be life threatening if not treated promptly. Other medicines patients may
be taking could have a negative effect when taken with the study drug.
There is a chance that the study drug may not help to lower patient*s risk of
excessive bleeding or it might worsen. Patients may have pain, bleeding,
swelling, or bruising around the vein where their blood is collected. There may
be a risk of infection from any blood draw. Patients may feel dizzy or patients
may feel faint. The procedures in this study may have risks that are not known
at this time.
Hayden Ave 95
Lexington MA 02421
US
Hayden Ave 95
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
1. Subject or legally authorized representative willing to sign
e-consent/written informed consent form.
2. Subjects >=18 years of age at enrollment.
3. Subject currently on treatment with oral Factor Xa inhibitor
(rivaroxaban, apixaban, edoxaban).
4. In the opinion of the surgeon, the subject requires urgent surgery/procedure
that is associated with high-risk of intraoperative bleeding within 15 hours of
the last Factor Xa inhibitor dose and requires a reversal agent for suspected
direct oral Factor Xa inhibitor-related coagulopathy. In subjects who are
beyond the 15-hour window,
eligibility requires proof of elevated plasma anti FXa levels using either
specific DOAC-calibrated (apixaban, rivaroxaban or edoxaban) anti-FXa
levels of > 75ng/mL, or heparin-calibrated anti-FXa assay levels of > 0.5
IU/mL at screening.
5. Women of childbearing potential should have a negative pregnancy test
documented prior to enrollment.
Exclusion criteria
1. The subject has an expected survival of less than 30 days, even with best
available medical and surgical care.
2. Recent history (within 90 days prior to screening) of venous
thromboembolism, myocardial infarction (MI), DIC, ischemic stroke, transient
ischemic attack, hospitalization for unstable angina pectoris or severe or
critical coronavirus 2 (SARS-CoV-2) infection.
3. Active major bleeding defined as bleeding that requires surgery or
transfusion of >2 units of PRBC or intracranial hemorrhage with the
exception of subacute and chronic subdural hemorrhages with a Glasgow
Coma Score (GCS) >= 9
4. Polytrauma for which reversal of Factor Xa-inhibition alone would not
be sufficient to achieve hemostasis.
5. Known prothrombotic disorder including primary antiphospholipid syndrome,
antithrombin-3 deficiency, homozygous protein C deficiency, homozygous protein
S deficiency, and homozygous factor V Leiden.
6. Known bleeding disorder (eg, platelet function disorder, hemophilia, Von
Willebrand disease, or coagulation factor deficiency).
7. Platelet count <50,000/µL.
8. History of heparin-induced thrombocytopenia.
9. Administration of procoagulant drugs (eg, non-study prothrombin complex
concentrates (PCCs), recombinant Factor VIIa) or blood products (transfusion of
whole blood, fresh frozen plasma, cryoglobulins, plasma fractions, or
platelets) within 7 days before enrollment. (Note: administration of PRBCs for
hemoglobin correction,
tranexamic acid or aminocaproic acid are not exclusion criteria).
10. Planned use of procoagulant drugs (eg, Vitamin K, non-study PCCs,
recombinant Factor VIIa) or blood products
(transfusion of whole blood, fresh frozen plasma, cryoglobulins, plasma
fractions, or platelets) after enrollment but before the investigational
product infusion is initiated (Note: administration of PRBCs for hemoglobin
correction tranexamic
acid or aminocaproic acid are not exclusion criteria)
11. Administration of unfractionated heparin within 2 hours before
randomization or low molecular weight heparin within 26hours before
randomization.
12. Hypersensitivity to PCC constituents, or any excipient of TAK-330.
13. Patients with history of confirmed immunoglobulin A (IgA)
deficiency with hypersensitivity reaction and antibodies to IgA.
14. Septic shock as defined by persistent hypotension requiring
vasopressors to maintain mean arterial pressure (MAP) >= 65mmHg and
having blood lactate > 2 mmol despite adequate volume resuscitation.
15. Acute or chronic liver failure (hepatic cirrhosis Child-PUGH score C).
16. Renal failure requiring dialysis.
17. Any other condition that could, in the opinion of the investigator, put
the subject at undue risk of harm if the subject were to participate in the
study.
18. Participation in another clinical study involving an investigational
product or device within 30 days prior to study enrollment, or planned
participation in another clinical study involving an investigational
product or device during the course of this study.
19. The use of PROTHROMPLEX TOTAL as SOC 4F-PCC.
20. Women who are breastfeeding at the time of enrollment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2022-503012-16-00 |
| EudraCT | EUCTR2021-004138-12-NL |
| ClinicalTrials.gov | NCT05156983 |
| CCMO | NL81011.056.22 |