Antithrombotic Agents, Arthroplasty, Replacement, Hip, Arthroplasty, Replacement, Knee, Blood Coagulation, Neuromuscular Blockade
Conditions
Brief summary
This study will assess the effect of reversal of neuromuscular blockade with sugammadex compared with reversal according to usual care (neostigmine or spontaneous reversal) on the incidence of post-surgical bleeding events and on coagulation parameters in participants undergoing hip fracture surgery or joint (hip/knee) replacement surgery with neuromuscular blockage induced by rocuronium or vecuronium.
Detailed description
Participants will be randomized to sugammadex or usual care in a 1:1 ratio.
Interventions
DRUGSugammadex
Sugammadex 4 mg/kg intravenously
DRUGneostigmine and glycopyrrolate or atropine
Neostigmine and glycopyrrolate or neostigmine and atropine administered intravenously per usual practice and per the product labels
DRUGPlacebo to neostigmine
Normal saline (NaCl 0.9%)
DRUGPlacebo to sugammadex
Normal saline (NaCl 0.9%)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be American Society of Anesthesiologists (ASA) Class 1, 2, or 3 * Must be scheduled for a hip fracture surgery or joint (hip or knee) replacement surgery under general anesthesia including the use of rocuronium or vecuronium for neuromuscular blockade * Must be: * Currently receiving thromboprophylactic (anti-clotting) therapy with low molecular weight heparin (LMWH) or unfractionated heparin (UFH), or * Planned to initiate thromboprophylactic therapy with LMWH or UFH prior to or during surgery, or * Currently receiving ongoing thromboprophylactic therapy with a vitamin K antagonist that has been temporarily substituted with peri-operative LMWH or UFH, and/or * Currently receiving ongoing thromboprophylactic therapy with low-dose aspirin or other antiplatelet therapy * Platelet count above the lower limit of normal range * Appropriate candidate for rapid reversal of neuromuscular blockade * Sexually active females must agree to use a medically accepted method of contraception through seven days after receiving protocol-specified medication
Exclusion criteria
* Anatomical malformations that may lead to difficult intubation * Neuromuscular disorder that may affect neuromuscular blockade * History of a coagulation disorder, bleeding diathesis, systemic lupus erythematosus or antiphospholipid syndrome * History or evidence of active abnormal bleeding or blood clotting within 30 days prior to screening * Significant hepatic dysfunction * Severe renal insufficiency * History or family history of malignant hyperthermia * Hypersensitivity or hypersensitivity-like reaction to sugammadex, muscle relaxants, or other medications used during general anesthesia * Planned intravenous administration of toremifene and/or fusidic acid within 24 hours before or within 24 hours after study medication * Recent, severe trauma * Body Mass Index (BMI) \> 35 * Any contraindication to administration of sugammadex or neostigmine/glycopyrrolate (or neostigmine/atropine) * Pregnant or intends to become pregnant between randomization and the Day 30 follow-up visit * Breast-feeding * Previously treated with sugammadex or participated in a sugammadex clinical trial * Has an active hip/knee infection and is scheduled for revision surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 24 Hours After Study Drug Administration | Up to 24 hours post study drug administration | Post-treatment events of bleeding were evaluated by a medically-qualified, blinded member of the surgical team (Blinded Safety Assessor), in consultation with the surgeon, to determine if an event was a suspected, unanticipated adverse event of bleeding (SUAEB). A SUAEB is an event of bleeding outside the usual boundaries of expectations for a participant (e.g., in amount of blood lost, prolonged duration of bleeding, or other factors) considering the type of procedure as well as participant's specific surgical experience and underlying risk of bleeding. In addition, blinded review of clinical and laboratory databases was performed to identify any event potentially consistent with a SUAEB; these were reviewed by the Blinded Safety Assessor, who determined if any was a SUAEB. All SUAEBs were evaluated by a blinded external Adjudication Committee, which classified each as either: 1) a major bleeding event, 2) a non-major bleeding event, or 3) not an unanticipated event of bleeding. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration | Baseline, 10 and 60 minutes post study drug administration | Change from baseline in PT(INR) is identified in study protocol as an Other Secondary Outcome Measure. Blood samples for determination of PT(INR) values were obtained at baseline and at 10 and 60 minutes after study drug administration. PT(INR) is a performance indicator measuring the efficacy of the extrinsic and common blood coagulation (blood clotting) pathways. The INR is the ratio of a participant's prothrombin time to a normal (control) sample, raised to the power of the International Sensitivity Index (ISI) value for the analytical system used (INR = \[PT-Test/PT-Normal\]\^ISI). Higher values of PT(INR) indicate a reduction in the clotting tendency of blood. |
| Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 14 Days After Study Drug Administration | Up to 14 days post study drug administration | This Measure is identified in study protocol as an Other Secondary Outcome Measure. Post-treatment events of bleeding were evaluated by a medically-qualified, blinded member of the surgical team (Blinded Safety Assessor), in consultation with the surgeon, to determine if an event was a suspected, unanticipated adverse event of bleeding (SUAEB). A SUAEB is an event of bleeding outside the usual boundaries of expectations for a participant considering the type of procedure as well as participant's specific surgical experience and underlying risk of bleeding. In addition, blinded review of clinical and laboratory databases was performed to identify any event potentially consistent with a SUAEB; these were reviewed by the Blinded Safety Assessor, who determined if any was a SUAEB. All SUAEBs were evaluated by a blinded external Adjudication Committee, which classified each as either: 1) a major bleeding event, 2) a non-major bleeding event, or 3) not an unanticipated event of bleeding. |
| Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 24 Hours After Study Drug Administration | Up to 24 hours post study drug administration | This Measure is identified in study protocol as an Other Secondary Outcome Measure. All SUAEB were evaluated by a blinded external Adjudication Committee. Major bleeding event (MBE) = one or more of the following: 1) Fatal bleeding; 2) Bleeding that is symptomatic and occurs in critical area/organ, in a non-operated joint, or is intramuscular with compartment syndrome; 3) Extrasurgical site bleeding causing a fall in hemoglobin (Hgb) level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red blood cells (RBCs), occurring within 24 hours of the bleeding; 4) Surgical site bleeding requiring second intervention, or bleeding at operated joint that interferes with rehabilitation; or 5) Surgical site bleeding that is unexpected/prolonged and/or causes hemodynamic instability, with fall in Hgb level of at least 20 g/L (1.24 mmol/L) or transfusion of at least two units of whole blood or RBCs, occurring within 24 hours of the bleeding. |
| Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 14 Days After Study Drug Administration | Up to 14 days post study drug administration | This Measure is identified in study protocol as an Other Secondary Outcome Measure. All SUAEB were evaluated by a blinded external Adjudication Committee. MBE = one or more of the following: 1) Fatal bleeding; 2) Bleeding that is symptomatic and occurs in critical area/organ, in a non-operated joint, or is intramuscular with compartment syndrome; 3) Extrasurgical site bleeding causing a fall in Hgb level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or RBCs, occurring within 24 hours of the bleeding; 4) Surgical site bleeding requiring second intervention, or bleeding at operated joint that interferes with rehabilitation; or 5) Surgical site bleeding that is unexpected/prolonged and/or causes hemodynamic instability, with fall in Hgb level of at least 20 g/L (1.24 mmol/L) or transfusion of at least two units of whole blood or RBCs, occurring within 24 hours of the bleeding. |
| Number of Participants With One or More Adjudicated Venous Thromboembolic (VTE) Events With Onset Within 14 Days After Study Drug Administration | Up to 14 days post study drug administration | This Measure is identified in study protocol as an Other Secondary Outcome Measure. Suspected symptomatic VTE events were evaluated by a blinded external Adjudication Committee. The confirmation of a VTE event was based on determination of a clinically meaningful venous thrombosis (e.g., pulmonary embolism or deep vein thrombosis). |
| Number of Participants With One or More Adjudicated Events of Anaphylaxis With Onset Within 14 Days After Study Drug Administration | Up to 14 days post study drug administration | This Measure is identified in study protocol as an Other Secondary Outcome Measure. Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Adverse events suggestive of hypersensitivity which met defined criteria (e.g., serious event) and/or suspected events of anaphylaxis were evaluated by a blinded external Adjudication Committee to determine whether such events met either of the following two criteria for anaphylaxis (Sampson et al. J Allergy Clin Immunol 2006;117:391-7) - 1. Acute onset of an illness with involvement of the skin, mucosal tissue or both, and at least one of the following: a) respiratory compromise, b) reduced blood pressure (BP) or associated symptoms of end-organ dysfunction. 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that participant: a) involvement of the skin-mucosal tissue, b) respiratory compromise, c) reduced BP or associated symptoms, d) persistent gastrointestinal symptoms. |
| Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration | Baseline, 10 and 60 minutes post study drug administration | Change from baseline in aPTT is identified in study protocol as the Key Secondary Outcome Measure. Blood samples for determination of aPTT values were obtained at baseline and at 10 and 60 minutes after study drug administration. aPTT is a performance indicator measuring the efficacy of the intrinsic and common blood coagulation (blood clotting) pathways. Higher values of aPTT indicate a reduction in the clotting tendency of blood. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Total Transfusion Volume in Participants Who Required Postoperative Transfusion | From end of study drug administration through approximately 120 hours after study drug administration | Among participants who received a transfusion unit (e.g., whole blood, packed RBCs, cell saver RBCs, fresh frozen plasma, platelets) that started after study drug administration and within 120 hours after study drug administration (or within 48 hours after any previous \[i.e., predose\] transfusion for participants who had received a previous transfusion), the total volume of blood transfused post study drug was calculated. The volume of blood transfused post study drug (using linear interpolation when transfusions were ongoing at the time of study drug administration) was converted to grams of Hgb transfused, using RBC concentration information received from the investigators. The sum of Hgb transfused was standardized to normal volume Hgb in homologous whole blood, using 20 g/dL Hgb for calculation of the standardized volume. |
| Postoperative Changes in Hgb Concentrations Using the Bleeding Index | Baseline and Visit 3 (24-48 hours post study drug administration) | The Bleeding Index was used to describe postoperative changes in Hgb concentrations at Visit 3. Bleeding Index = Hgb level at Visit 3 - Hgb level at baseline, adjusted for the amount of RBCs transfused. Missing baseline Hgb values were imputed using the overall mean Hgb value at baseline. |
| Number of Participants With One or More Postoperative Anemia Adverse Events With Onset Within 72 Hours After Study Drug Administration | Up to 72 hours post study drug administration | This measure is the incidence of postoperative anaemia with an onset within 72 hours after study drug administration. A participant is included in the count for this measure if an adverse event with any of the following event terms occurred in the participant with onset within the defined time frame: postoperative anaemia, anaemia, haemorrhagic anaemia, haemoglobin decreased or haemoglobin S decreased. |
| Number of Participants Requiring Any Postoperative Transfusion | From end of study drug administration through approximately 120 hours after study drug administration | The number of participants who received a transfusion unit (e.g., whole blood, packed RBCs, cell saver RBCs, fresh frozen plasma, platelets) that started after study drug administration and within 120 hours after study drug administration (or within 48 hours after any previous \[i.e., predose\] transfusion for participants who had received a previous transfusion) was determined. |
| Postoperative Drainage Volume Within 24 Hours After Study Drug Administration | Up to 24 hours post study drug administration | The total volume of postoperative drainage from the surgical site over the 24 hours after study drug administration was recorded. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sugammadex For participants in this Arm assigned to planned active reversal of neuromuscular blockade: single intravenous (IV) administration of sugammadex 4 mg/kg and single IV administration of placebo (normal saline \[NaCl 0.9%\] to match volume of neostigmine/glycopyrrolate \[or neostigmine/atropine\] that would have been administered). For participants in this Arm assigned to planned spontaneous recovery from neuromuscular blockade: single IV administration of sugammadex 4 mg/kg. | 596 |
| Usual Care For participants in this Arm assigned to planned active reversal of neuromuscular blockade: single IV administration of neostigmine (up to a maximum dose of 5 mg) with glycopyrrolate or atropine and single IV administration of placebo (normal saline \[NaCl 0.9%\] to match volume of sugammadex that would have been administered). For participants in this Arm assigned to planned spontaneous recovery from neuromuscular blockade: single IV administration of placebo (normal saline \[NaCl 0.9%\] to match volume of sugammadex that would have been administered). | 588 |
| Total | 1,184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Did Not Meet Protocol Eligibility | 0 | 2 |
| Overall Study | Lost to Follow-up | 14 | 20 |
| Overall Study | Never Entered Follow-up | 2 | 1 |
| Overall Study | Not Treated | 3 | 11 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Sugammadex | Total | Usual Care |
|---|---|---|---|
| Activated Partial Thromboplastin Time (aPTT) | 31.14 seconds STANDARD_DEVIATION 4.38 | 31.08 seconds STANDARD_DEVIATION 4.26 | 31.01 seconds STANDARD_DEVIATION 4.14 |
| Age, Continuous | 66.7 years STANDARD_DEVIATION 12 | 66.7 years STANDARD_DEVIATION 11.7 | 66.6 years STANDARD_DEVIATION 11.3 |
| Prothrombin Time (International Normalized Ratio) (PT[INR]) | 1.121 ratio STANDARD_DEVIATION 0.159 | 1.117 ratio STANDARD_DEVIATION 0.147 | 1.114 ratio STANDARD_DEVIATION 0.132 |
| Sex: Female, Male Female | 326 Participants | 666 Participants | 340 Participants |
| Sex: Female, Male Male | 270 Participants | 518 Participants | 248 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 491 / 596 | 499 / 588 |
| serious Total, serious adverse events | 39 / 596 | 40 / 588 |
Outcome results
Primary
Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 24 Hours After Study Drug Administration
Post-treatment events of bleeding were evaluated by a medically-qualified, blinded member of the surgical team (Blinded Safety Assessor), in consultation with the surgeon, to determine if an event was a suspected, unanticipated adverse event of bleeding (SUAEB). A SUAEB is an event of bleeding outside the usual boundaries of expectations for a participant (e.g., in amount of blood lost, prolonged duration of bleeding, or other factors) considering the type of procedure as well as participant's specific surgical experience and underlying risk of bleeding. In addition, blinded review of clinical and laboratory databases was performed to identify any event potentially consistent with a SUAEB; these were reviewed by the Blinded Safety Assessor, who determined if any was a SUAEB. All SUAEBs were evaluated by a blinded external Adjudication Committee, which classified each as either: 1) a major bleeding event, 2) a non-major bleeding event, or 3) not an unanticipated event of bleeding.
Time frame: Up to 24 hours post study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 24 Hours After Study Drug Administration | 17 participants |
| Usual Care | Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 24 Hours After Study Drug Administration | 24 participants |
Comparison: Cochran-Mantel-Haenszel method was stratified for renal function (estimated creatinine clearance \< or ≥ 60 mL/min) and prophylactic antithrombotic therapy (including low molecular weight heparin \[LMWH\], including unfractionated heparin \[UFH\], or not including either LMWH or UFH)95% CI: [0.38, 1.29]Cochran-Mantel-Haenszel
Secondary
Number of Participants With One or More Adjudicated Events of Anaphylaxis With Onset Within 14 Days After Study Drug Administration
This Measure is identified in study protocol as an Other Secondary Outcome Measure. Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Adverse events suggestive of hypersensitivity which met defined criteria (e.g., serious event) and/or suspected events of anaphylaxis were evaluated by a blinded external Adjudication Committee to determine whether such events met either of the following two criteria for anaphylaxis (Sampson et al. J Allergy Clin Immunol 2006;117:391-7) - 1. Acute onset of an illness with involvement of the skin, mucosal tissue or both, and at least one of the following: a) respiratory compromise, b) reduced blood pressure (BP) or associated symptoms of end-organ dysfunction. 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that participant: a) involvement of the skin-mucosal tissue, b) respiratory compromise, c) reduced BP or associated symptoms, d) persistent gastrointestinal symptoms.
Time frame: Up to 14 days post study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants With One or More Adjudicated Events of Anaphylaxis With Onset Within 14 Days After Study Drug Administration | 0 participants |
| Usual Care | Number of Participants With One or More Adjudicated Events of Anaphylaxis With Onset Within 14 Days After Study Drug Administration | 0 participants |
Secondary
Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 14 Days After Study Drug Administration
This Measure is identified in study protocol as an Other Secondary Outcome Measure. Post-treatment events of bleeding were evaluated by a medically-qualified, blinded member of the surgical team (Blinded Safety Assessor), in consultation with the surgeon, to determine if an event was a suspected, unanticipated adverse event of bleeding (SUAEB). A SUAEB is an event of bleeding outside the usual boundaries of expectations for a participant considering the type of procedure as well as participant's specific surgical experience and underlying risk of bleeding. In addition, blinded review of clinical and laboratory databases was performed to identify any event potentially consistent with a SUAEB; these were reviewed by the Blinded Safety Assessor, who determined if any was a SUAEB. All SUAEBs were evaluated by a blinded external Adjudication Committee, which classified each as either: 1) a major bleeding event, 2) a non-major bleeding event, or 3) not an unanticipated event of bleeding.
Time frame: Up to 14 days post study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 14 Days After Study Drug Administration | 24 participants |
| Usual Care | Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 14 Days After Study Drug Administration | 27 participants |
95% CI: [-3, 1.8]Miettinen and Nurminen
Secondary
Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 14 Days After Study Drug Administration
This Measure is identified in study protocol as an Other Secondary Outcome Measure. All SUAEB were evaluated by a blinded external Adjudication Committee. MBE = one or more of the following: 1) Fatal bleeding; 2) Bleeding that is symptomatic and occurs in critical area/organ, in a non-operated joint, or is intramuscular with compartment syndrome; 3) Extrasurgical site bleeding causing a fall in Hgb level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or RBCs, occurring within 24 hours of the bleeding; 4) Surgical site bleeding requiring second intervention, or bleeding at operated joint that interferes with rehabilitation; or 5) Surgical site bleeding that is unexpected/prolonged and/or causes hemodynamic instability, with fall in Hgb level of at least 20 g/L (1.24 mmol/L) or transfusion of at least two units of whole blood or RBCs, occurring within 24 hours of the bleeding.
Time frame: Up to 14 days post study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 14 Days After Study Drug Administration | 18 participants |
| Usual Care | Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 14 Days After Study Drug Administration | 23 participants |
95% CI: [-3.1, 1.2]Miettinen and Nurminen
Secondary
Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 24 Hours After Study Drug Administration
This Measure is identified in study protocol as an Other Secondary Outcome Measure. All SUAEB were evaluated by a blinded external Adjudication Committee. Major bleeding event (MBE) = one or more of the following: 1) Fatal bleeding; 2) Bleeding that is symptomatic and occurs in critical area/organ, in a non-operated joint, or is intramuscular with compartment syndrome; 3) Extrasurgical site bleeding causing a fall in hemoglobin (Hgb) level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red blood cells (RBCs), occurring within 24 hours of the bleeding; 4) Surgical site bleeding requiring second intervention, or bleeding at operated joint that interferes with rehabilitation; or 5) Surgical site bleeding that is unexpected/prolonged and/or causes hemodynamic instability, with fall in Hgb level of at least 20 g/L (1.24 mmol/L) or transfusion of at least two units of whole blood or RBCs, occurring within 24 hours of the bleeding.
Time frame: Up to 24 hours post study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 24 Hours After Study Drug Administration | 12 participants |
| Usual Care | Number of Participants With One or More Adjudicated Major Events of Bleeding With Onset Within 24 Hours After Study Drug Administration | 20 participants |
95% CI: [-3.4, 0.5]Miettinen and Nurminen
Secondary
Number of Participants With One or More Adjudicated Venous Thromboembolic (VTE) Events With Onset Within 14 Days After Study Drug Administration
This Measure is identified in study protocol as an Other Secondary Outcome Measure. Suspected symptomatic VTE events were evaluated by a blinded external Adjudication Committee. The confirmation of a VTE event was based on determination of a clinically meaningful venous thrombosis (e.g., pulmonary embolism or deep vein thrombosis).
Time frame: Up to 14 days post study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants With One or More Adjudicated Venous Thromboembolic (VTE) Events With Onset Within 14 Days After Study Drug Administration | 5 participants |
| Usual Care | Number of Participants With One or More Adjudicated Venous Thromboembolic (VTE) Events With Onset Within 14 Days After Study Drug Administration | 3 participants |
95% CI: [-0.7, 1.5]Miettinen and Nurminen
Secondary
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration
Change from baseline in aPTT is identified in study protocol as the Key Secondary Outcome Measure. Blood samples for determination of aPTT values were obtained at baseline and at 10 and 60 minutes after study drug administration. aPTT is a performance indicator measuring the efficacy of the intrinsic and common blood coagulation (blood clotting) pathways. Higher values of aPTT indicate a reduction in the clotting tendency of blood.
Time frame: Baseline, 10 and 60 minutes post study drug administration
Population: Participants in APaT population who had baseline and at least one post baseline aPTT measurement within defined assessment window (10 or 60 minutes post study drug).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sugammadex | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration | 10 minutes (Sugammadex n=525, Usual Care n=507) | 6.0 percent change | Standard Deviation 22.4 |
| Sugammadex | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration | 60 minutes (Sugammadex n=523, Usual Care n=505) | 0.4 percent change | Standard Deviation 29.1 |
| Usual Care | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration | 10 minutes (Sugammadex n=525, Usual Care n=507) | -0.1 percent change | Standard Deviation 13.6 |
| Usual Care | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration | 60 minutes (Sugammadex n=523, Usual Care n=505) | -1.2 percent change | Standard Deviation 22.7 |
Comparison: Model was restricted to have no difference between treatment groups for baseline assessment, and was adjusted for center, usual care group (active reversal or spontaneous recovery), renal function (estimated creatinine clearance \< or ≥ 60 mL/min), prophylactic antithrombotic therapy (including LMWH, including UFH, or not including either LMWH or UFH), type of hip/knee surgical procedure, and the interaction of time by treatment.95% CI: [3.7, 7.3]Constrained Longitudinal Data Analysis
Comparison: Model was restricted to have no difference between treatment groups for baseline assessment, and was adjusted for center, usual care group (active reversal or spontaneous recovery), renal function (estimated creatinine clearance \< or ≥ 60 mL/min), prophylactic antithrombotic therapy (including LMWH, including UFH, or not including either LMWH or UFH), type of hip/knee surgical procedure, and the interaction of time by treatment.95% CI: [-0.9, 2.8]Constrained Longitudinal Data Analysis
Secondary
Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration
Change from baseline in PT(INR) is identified in study protocol as an Other Secondary Outcome Measure. Blood samples for determination of PT(INR) values were obtained at baseline and at 10 and 60 minutes after study drug administration. PT(INR) is a performance indicator measuring the efficacy of the extrinsic and common blood coagulation (blood clotting) pathways. The INR is the ratio of a participant's prothrombin time to a normal (control) sample, raised to the power of the International Sensitivity Index (ISI) value for the analytical system used (INR = \[PT-Test/PT-Normal\]\^ISI). Higher values of PT(INR) indicate a reduction in the clotting tendency of blood.
Time frame: Baseline, 10 and 60 minutes post study drug administration
Population: Participants in APaT population who had baseline and at least one post baseline PT(INR) measurement within defined assessment window (10 or 60 minutes post study drug).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sugammadex | Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration | 10 minutes (Sugammadex n=526, Usual Care n=507) | 8.0 percent change | Standard Deviation 63.4 |
| Sugammadex | Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration | 60 minutes (Sugammadex n=524, Usual Care n=505) | 8.9 percent change | Standard Deviation 79.8 |
| Usual Care | Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration | 10 minutes (Sugammadex n=526, Usual Care n=507) | 2.5 percent change | Standard Deviation 14.3 |
| Usual Care | Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration | 60 minutes (Sugammadex n=524, Usual Care n=505) | 3.4 percent change | Standard Deviation 23.2 |
Comparison: Model was restricted to have no difference between treatment groups for baseline assessment, and was adjusted for center, usual care group (active reversal or spontaneous recovery), renal function (estimated creatinine clearance \< or ≥ 60 mL/min), prophylactic antithrombotic therapy (including LMWH, including UFH, or not including either LMWH or UFH), type of hip/knee surgical procedure, and the interaction of time by treatment.95% CI: [1.3, 4.7]Constrained Longitudinal Data Analysis
Comparison: Model was restricted to have no difference between treatment groups for baseline assessment, and was adjusted for center, usual care group (active reversal or spontaneous recovery), renal function (estimated creatinine clearance \< or ≥ 60 mL/min), prophylactic antithrombotic therapy (including LMWH, including UFH, or not including either LMWH or UFH), type of hip/knee surgical procedure, and the interaction of time by treatment.95% CI: [-1, 2.9]Constrained Longitudinal Data Analysis
Other Pre-specified
Number of Participants Requiring Any Postoperative Transfusion
The number of participants who received a transfusion unit (e.g., whole blood, packed RBCs, cell saver RBCs, fresh frozen plasma, platelets) that started after study drug administration and within 120 hours after study drug administration (or within 48 hours after any previous \[i.e., predose\] transfusion for participants who had received a previous transfusion) was determined.
Time frame: From end of study drug administration through approximately 120 hours after study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants Requiring Any Postoperative Transfusion | 221 participants |
| Usual Care | Number of Participants Requiring Any Postoperative Transfusion | 227 participants |
Comparison: Miettinen and Nurminen Method was adjusted for strata (renal function and use of prophylactic antithrombotic therapy) and investigational site95% CI: [-7.4, 2]Miettinen and Nurminen
Other Pre-specified
Number of Participants With One or More Postoperative Anemia Adverse Events With Onset Within 72 Hours After Study Drug Administration
This measure is the incidence of postoperative anaemia with an onset within 72 hours after study drug administration. A participant is included in the count for this measure if an adverse event with any of the following event terms occurred in the participant with onset within the defined time frame: postoperative anaemia, anaemia, haemorrhagic anaemia, haemoglobin decreased or haemoglobin S decreased.
Time frame: Up to 72 hours post study drug administration
Population: APaT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sugammadex | Number of Participants With One or More Postoperative Anemia Adverse Events With Onset Within 72 Hours After Study Drug Administration | 124 participants |
| Usual Care | Number of Participants With One or More Postoperative Anemia Adverse Events With Onset Within 72 Hours After Study Drug Administration | 132 participants |
95% CI: [-6.3, 3.1]Miettinen and Nurminen
Other Pre-specified
Postoperative Changes in Hgb Concentrations Using the Bleeding Index
The Bleeding Index was used to describe postoperative changes in Hgb concentrations at Visit 3. Bleeding Index = Hgb level at Visit 3 - Hgb level at baseline, adjusted for the amount of RBCs transfused. Missing baseline Hgb values were imputed using the overall mean Hgb value at baseline.
Time frame: Baseline and Visit 3 (24-48 hours post study drug administration)
Population: APaT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugammadex | Postoperative Changes in Hgb Concentrations Using the Bleeding Index | -15.7 g/L | Standard Deviation 15.7 |
| Usual Care | Postoperative Changes in Hgb Concentrations Using the Bleeding Index | -17.4 g/L | Standard Deviation 17.1 |
Comparison: Generalized Linear Model was adjusted for strata (renal function and use of prophylactic antithrombotic therapy), investigational site and baseline hemoglobin value.95% CI: [-0.4, 3.1]Generalized Linear Model
Other Pre-specified
Postoperative Drainage Volume Within 24 Hours After Study Drug Administration
The total volume of postoperative drainage from the surgical site over the 24 hours after study drug administration was recorded.
Time frame: Up to 24 hours post study drug administration
Population: APaT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugammadex | Postoperative Drainage Volume Within 24 Hours After Study Drug Administration | 464 mL | Standard Deviation 367.5 |
| Usual Care | Postoperative Drainage Volume Within 24 Hours After Study Drug Administration | 476 mL | Standard Deviation 375.3 |
Comparison: Generalized Linear Model was adjusted for strata (renal function and use of prophylactic antithrombotic therapy) and investigational site.95% CI: [-45, 30.5]Generalized Linear Model
Other Pre-specified
Total Transfusion Volume in Participants Who Required Postoperative Transfusion
Among participants who received a transfusion unit (e.g., whole blood, packed RBCs, cell saver RBCs, fresh frozen plasma, platelets) that started after study drug administration and within 120 hours after study drug administration (or within 48 hours after any previous \[i.e., predose\] transfusion for participants who had received a previous transfusion), the total volume of blood transfused post study drug was calculated. The volume of blood transfused post study drug (using linear interpolation when transfusions were ongoing at the time of study drug administration) was converted to grams of Hgb transfused, using RBC concentration information received from the investigators. The sum of Hgb transfused was standardized to normal volume Hgb in homologous whole blood, using 20 g/dL Hgb for calculation of the standardized volume.
Time frame: From end of study drug administration through approximately 120 hours after study drug administration
Population: Participants in APaT population who received a transfusion unit that started after study drug administration and within 120 hours after study drug administration (or within 48 hours after any previous \[i.e., predose\] transfusion for participants who had received a previous transfusion)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Sugammadex | Total Transfusion Volume in Participants Who Required Postoperative Transfusion | 335 mL | Geometric Coefficient of Variation 74 |
| Usual Care | Total Transfusion Volume in Participants Who Required Postoperative Transfusion | 345 mL | Geometric Coefficient of Variation 84.5 |
Comparison: Generalized Linear Model was applied to transfusion volume transformed to the log-scale, adjusted for strata (renal function and use of prophylactic antithrombotic therapy) and investigational site. Result and 95% Confidence Interval was transformed back to the original scale.95% CI: [0.98, 1.24]Generalized Linear Model