Reversal of Neuromuscular Blockade With Sugammadex or Usual Care in Hip Fracture Surgery or Joint (Hip/Knee) Replacement (P07038)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01422304
First received: August 22, 2011
Last updated: May 14, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Neuromuscular Blockade
Arthroplasty, Replacement, Hip
Arthroplasty, Replacement, Knee
Blood Coagulation
Antithrombotic Agents
Drug: Sugammadex
Drug: neostigmine and glycopyrrolate or atropine
Drug: Placebo to neostigmine
Drug: Placebo to sugammadex
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Controlled, Parallel-group, Double-blind Trial of Sugammadex or Usual Care (Neostigmine or Spontaneous Recovery) for Reversal of Rocuronium- or Vecuronium-induced Neuromuscular Blockade in Patients Receiving Thromboprophylaxis and Undergoing Hip Fracture Surgery or Joint (Hip/Knee) Replacement (Protocol No. P07038)

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 24 Hours After Study Drug Administration [ Time Frame: Up to 24 hours post study drug administration ] [ Designated as safety issue: Yes ]
    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 Outcome Measures:
  • Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration [ Time Frame: Baseline, 10 and 60 minutes post study drug administration ] [ Designated as safety issue: Yes ]
    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.

  • Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration [ Time Frame: Baseline, 10 and 60 minutes post study drug administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 14 days post study drug administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 24 hours post study drug administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 14 days post study drug administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 14 days post study drug administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 14 days post study drug administration ] [ Designated as safety issue: Yes ]
    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.


Other Outcome Measures:
  • Postoperative Drainage Volume Within 24 Hours After Study Drug Administration [ Time Frame: Up to 24 hours post study drug administration ] [ Designated as safety issue: Yes ]
    The total volume of postoperative drainage from the surgical site over the 24 hours after study drug administration was recorded.

  • Number of Participants Requiring Any Postoperative Transfusion [ Time Frame: From end of study drug administration through approximately 120 hours after study drug administration ] [ Designated as safety issue: Yes ]
    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.

  • Total Transfusion Volume in Participants Who Required Postoperative Transfusion [ Time Frame: From end of study drug administration through approximately 120 hours after study drug administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline and Visit 3 (24-48 hours post study drug administration) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to 72 hours post study drug administration ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 1198
Study Start Date: October 2011
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sugammadex
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
Sugammadex 4 mg/kg intravenously
Other Name: SCH 900616, MK-8616
Drug: Placebo to neostigmine
Normal saline (NaCl 0.9%)
Experimental: Usual Care
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
Neostigmine and glycopyrrolate or neostigmine and atropine administered intravenously per usual practice and per the product labels
Drug: Placebo to sugammadex
Normal saline (NaCl 0.9%)

Detailed Description:

Participants will be randomized to sugammadex or usual care in a 1:1 ratio.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

No publications provided

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01422304     History of Changes
Other Study ID Numbers: P07038, 2011-001201-27, MK-8616-059
Study First Received: August 22, 2011
Results First Received: August 19, 2013
Last Updated: May 14, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Hip Fractures
Femoral Fractures
Fractures, Bone
Wounds and Injuries
Hip Injuries
Leg Injuries
Atropine
Glycopyrrolate
Neostigmine
Vecuronium Bromide
Rocuronium
Adjuvants, Anesthesia
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Arrhythmia Agents
Cardiovascular Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Parasympatholytics
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2014