Reversal of Neuromuscular Blockade With Sugammadex or Usu... | NCT01422304

ID	Type	Description	Link
2011-001201-27	EudraCT Number
MK-8616-059	Other Identifier	Merck protocol number

Label	Type	Description	Intervention Names
Sugammadex	Experimental	Prior to randomization, participants will be assigned to planned active reversal or planned spontaneous recovery by the anesthesiologist according to the recovery method the anesthesiologist would have chosen if the participant were not in the study. In this treatment arm, participants assigned to planned active reversal will receive sugammadex and placebo to neostigmine, and participants assigned to planned spontaneous recovery will receive sugammadex. Study drug will be administered after the last dose of rocuronium or vecuronium and after wound closure.	Drug: Sugammadex Drug: Placebo to neostigmine
Usual Care	Experimental	Prior to randomization, participants will be assigned to planned active reversal or planned spontaneous recovery by the anesthesiologist according to the recovery method the anesthesiologist would have chosen if the participant were not in the study. In this treatment arm, participants assigned to planned active reversal will receive neostigmine and placebo to sugammadex, and participants assigned to planned spontaneous recovery will receive placebo to sugammadex. Study drug will be administered after the last dose of rocuronium or vecuronium and after wound closure.	Drug: neostigmine and glycopyrrolate or atropine Drug: Placebo to sugammadex

Name	Type	Description	Arm Group Labels	Other Names
Sugammadex	Drug	Sugammadex 4 mg/kg intravenously	Sugammadex	SCH 900616, MK-8616

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	Up to 24 hours post study drug administration

Secondary Outcomes

Measure	Description	Time Frame
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.

Other Outcomes

Measure	Description	Time Frame
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.	Up to 24 hours post study drug administration
Number of Participants Requiring Any Postoperative Transfusion

Eligibility Module

Eligibility Criteria

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

PubMed Identifier	Type	Citation	Retractions
25208233	Result	Rahe-Meyer N, Fennema H, Schulman S, Klimscha W, Przemeck M, Blobner M, Wulf H, Speek M, McCrary Sisk C, Williams-Herman D, Woo T, Szegedi A. Effect of reversal of neuromuscular blockade with sugammadex versus usual care on bleeding risk in a randomized study of surgical patients. Anesthesiology. 2014 Nov;121(5):969-77. doi: 10.1097/ALN.0000000000000424.

ID	Title	Description
FG000	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.

ID	Title	Description
BG000	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.
BG001	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).
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG000596 BG001588 BG0021184

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

APaT population

Posted

Number

participants

Up to 24 hours post study drug administration

ID	Title	Description
OG000	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.
OG001	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).

Units	Counts
Participants	OG000596 OG001588

Title

Denominators

Categories

Title	Measurements
	OG00017 OG00124

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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)	Cochran-Mantel-Haenszel				Risk Ratio (RR)	0.70			2-Sided	95	0.38	1.29			Relative risk is Sugammadex versus Usual Care		Superiority or Other (legacy)

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.

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).

Posted

Mean

Standard Deviation

percent change

Baseline, 10 and 60 minutes post study drug administration

ID	Title	Description
OG000	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.
OG001	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).

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.

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).

Posted

Mean

Standard Deviation

percent change

Baseline, 10 and 60 minutes post study drug administration

ID	Title	Description
OG000	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.

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.

APaT population

Posted

Number

participants

Up to 14 days post study drug administration

ID	Title	Description
OG000	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.

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.

APaT population

Posted

Number

participants

Up to 24 hours post study drug administration

ID	Title	Description
OG000	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.

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.

APaT population

Posted

Number

participants

Up to 14 days post study drug administration

ID	Title	Description
OG000	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.

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).

APaT population

Posted

Number

participants

Up to 14 days post study drug administration

ID	Title	Description
OG000	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.
OG001	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).

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.

APaT population

Posted

Number

participants

Up to 14 days post study drug administration

ID	Title	Description
OG000	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.

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.

APaT population

Posted

Mean

Standard Deviation

Up to 24 hours post study drug administration

ID	Title	Description
OG000	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.
OG001	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).

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.

APaT population

Posted

Number

participants

From end of study drug administration through approximately 120 hours after study drug administration

ID	Title	Description
OG000	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.
OG001	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).

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.

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)

Posted

Geometric Mean

Geometric Coefficient of Variation

From end of study drug administration through approximately 120 hours after study drug administration

ID	Title	Description
OG000	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.

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.

APaT population

Posted

Mean

Standard Deviation

g/L

Baseline and Visit 3 (24-48 hours post study drug administration)

ID	Title	Description
OG000	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.
OG001	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).

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.

APaT population

Posted

Number

participants

Up to 72 hours post study drug administration

ID	Title	Description
OG000	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.
OG001	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).

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0011 events1 affected588 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0011 events1 affected588 at risk
Mitral valve stenosis	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Myocardial infarction	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Ventricular fibrillation	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Vitreous detachment	Eye disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Colitis ischaemic	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Subileus	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Tooth loss	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Asthenia	General disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Device breakage	General disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Device dislocation	General disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Drug withdrawal syndrome	General disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Impaired healing	General disorders	MedDRA 15.0	Systematic Assessment	EG0002 events2 affected596 at risk EG0014 events4 affected588 at risk
Pain	General disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Clostridial infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Nasopharyngitis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Pneumonia	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0012 events2 affected588 at risk
Post procedural infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Rotavirus infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Sepsis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Urinary tract infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Wound infection staphylococcal	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Anaemia postoperative	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0012 events2 affected588 at risk
Femoral nerve injury	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Incision site haematoma	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Periprosthetic fracture	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0012 events2 affected588 at risk
Post procedural haemorrhage	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Postoperative wound complication	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Seroma	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0002 events2 affected596 at risk EG0011 events1 affected588 at risk
Subcutaneous haematoma	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0002 events2 affected596 at risk EG0011 events1 affected588 at risk
Tendon rupture	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Wound dehiscence	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Wound haemorrhage	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Wound secretion	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0002 events2 affected596 at risk EG0014 events4 affected588 at risk
C-reactive protein increased	Investigations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Groin pain	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Joint range of motion decreased	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG0006 events6 affected596 at risk EG0011 events1 affected588 at risk
Joint swelling	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Muscle haemorrhage	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Osteonecrosis	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Chronic lymphocytic leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Malignant melanoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Nerve compression	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Paraesthesia	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Peripheral nerve lesion	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Reversible ischaemic neurological deficit	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0012 events1 affected588 at risk
Oliguria	Renal and urinary disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Renal failure	Renal and urinary disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Renal failure acute	Renal and urinary disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Apnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected596 at risk EG0011 events1 affected588 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0011 events1 affected588 at risk
Supportive care	Surgical and medical procedures	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0013 events3 affected588 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected596 at risk EG0010 events0 affected588 at risk
Haematoma	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected596 at risk EG0012 events2 affected588 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG00075 events72 affected596 at risk EG00174 events74 affected588 at risk
Constipation	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG000129 events128 affected596 at risk EG001148 events146 affected588 at risk
Nausea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG000138 events124 affected596 at risk EG001154 events139 affected588 at risk
Vomiting	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG00067 events64 affected596 at risk EG00174 events70 affected588 at risk
Oedema peripheral	General disorders	MedDRA 15.0	Systematic Assessment	EG00055 events53 affected596 at risk EG00150 events47 affected588 at risk
Pain	General disorders	MedDRA 15.0	Systematic Assessment	EG000112 events91 affected596 at risk EG001124 events101 affected588 at risk
Anaemia postoperative	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG00064 events63 affected596 at risk EG00166 events65 affected588 at risk
Procedural pain	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG000224 events203 affected596 at risk EG001259 events234 affected588 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG00033 events33 affected596 at risk EG00147 events45 affected588 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 15.0	Systematic Assessment	EG00084 events54 affected596 at risk EG00160 events40 affected588 at risk
Insomnia	Psychiatric disorders	MedDRA 15.0	Systematic Assessment	EG00050 events50 affected596 at risk EG00155 events54 affected588 at risk
Sleep disorder	Psychiatric disorders	MedDRA 15.0	Systematic Assessment	EG00090 events87 affected596 at risk EG00186 events84 affected588 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA 15.0	Systematic Assessment	EG00031 events26 affected596 at risk EG00138 events32 affected588 at risk
Haematoma	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG00061 events59 affected596 at risk EG00154 events53 affected588 at risk
Hypotension	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG00028 events27 affected596 at risk EG00140 events37 affected588 at risk

ID	Term
D016769	Embolism and Thrombosis
D014652	Vascular Diseases
D002318	Cardiovascular Diseases

ID	Term
D000077122	Sugammadex
D009388	Neostigmine
D006024	Glycopyrrolate
D001285	Atropine

ID	Term
D047408	gamma-Cyclodextrins
D003505	Cyclodextrins
D047028	Macrocyclic Compounds
D011083	Polycyclic Compounds
D003912	Dextrins
D013213	Starch
D005936	Glucans
D011134	Polysaccharides
D002241	Carbohydrates
D050338	Phenylammonium Compounds
D000644	Quaternary Ammonium Compounds
D000588	Amines
D009930	Organic Chemicals
D009861	Onium Compounds
D011759	Pyrrolidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D001286	Atropine Derivatives
D014326	Tropanes
D053961	Azabicyclo Compounds
D001372	Aza Compounds
D001533	Belladonna Alkaloids
D012991	Solanaceous Alkaloids
D000470	Alkaloids
D019086	Bridged Bicyclo Compounds, Heterocyclic
D006572	Heterocyclic Compounds, Bridged-Ring

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.			39	596	491	596
EG001	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).			40	588	499	588