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.

In a clinical study of healthy subjects (Trial 19.4.115), doses of 4 mg.kg-1
and 16 mg.kg-1 of sugammadex resulted in mean prolongations of activated
partial thromboplastin time (aPTT) and prothrombin time (PT) by up to 17-22% in
a dose dependent manner. These limited, mean aPTT and PT prolongations resolved
quickly (i.e., <= 30 minutes), and pooled analysis of the Phase II/III data from
the sugammadex development program did not indicate an increase in clinically
meaningful events of bleeding. However, to further investigate the potential
clinical relevance of these findings, the current study will investigate the
effects of (1) reversal of neuromuscular blockade using sugammadex at the
clinical dose of 4 mg.kg-1 and (2) reversal of neuromuscular blockade according
to usual care (neostigmine or spontaneous reversal) on adjudicated events of
bleeding and coagulation parameters in surgical patients at increased risk for
bleeding events due to concomitant administration of thromboprophylactic
therapy.

Primary Trial Objective:
To assess the effect of reversal of neuromuscular blockade with sugammadex 4
mg.kg-1 compared with reversal according to usual care (neostigmine or
spontaneous reversal) on the incidence of adjudicated postsurgical events of
bleeding over 24 hours, in patients receiving thromboprophylaxis and undergoing
hip fracture surgery or joint (hip/knee) replacement with neuromuscular
blockade induced by rocuronium or vecuronium.

Key Secondary Trial Objectives:
- To assess the effect of reversal of neuromuscular blockade with sugammadex 4
mg.kg-1 compared with reversal according to usual care (neostigmine or
spontaneous reversal) on activated partial thromboplastin time (aPTT) (with
values over a period of up to 2 hours in a subset of patients).
- To assess the safety of reversal of neuromuscular blockade with sugammadex 4
mg.kg-1 compared with reversal according to usual care (neostigmine or
spontaneous reversal).

This is a randomized, controlled, parallel-group, multi-site, 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. Patients for whom active reversal would have been
usual care will receive sugammadex or neostigmine (Usual Care Group 1).
Patients for whom spontaneous recovery would have been usual care will receive
sugammadex or placebo (Usual Care Group 2). Randomization to sugammadex or
usual care (1:1) will be stratified according to thromboprophylaxis (including
low molecular weight heparin [LMWH], including unfractionated heparin [UFH], or
not including either LMWH or UFH) and renal function (estimated creatinine
clearance < or >= 60 mL/min).

Duration of Participation:
Each patient will participate in the trial for approximately 56 days from the
time the patient signs the Informed Consent Form (ICF) through the final
contact. After a screening phase of up to 7 days, each patient will receive the
assigned treatment. The primary period of observation will be 24 hours or until
hospital discharge, whichever is sooner. A follow-up visit will occur 4 to 7
weeks after treatment.

- Treatment with either sugammadex, combination of neostigmine and atropine, or
placebo
- One follow-up visit 4-7 weeks after treatment

Sugammadex has been approved for use via the EU Centralised Procedure on 25
July 2008 and has been marketed since September 2008 as Bridion® in many EU
countries. It is currently approved in over 64 countries around the world. Over
890,000 patients have been exposed to sugammadex based on marketing sales data
[PSUR, 2009; PSUR, 2010 and PSUR, 2011].

Safety data of sugammadex has been collected from more than 32 trials conducted
in more than 2,500 surgical patients. In addition 664 healthy subjects have
been administered sugammadex in doses ranging from 0.5-96 mg/kg. The safety
profile has shown that sugammadex is generally safe and well tolerated. The
CCDS [2011] indicates that the undesirable effects of sugammadex include drug
hypersensitivity [Uncommon (>= 1/1000 to <1/100], anesthetic complication
[Common (>= 1/100 to <1/10)] which includes movements indicative of the
restoration of neuromuscular function (movement of a limb or the body or
coughing during the anaesthetic procedure or during surgery, grimacing, or
suckling on the endotracheal tube) and slow recovery from neuromuscular
blockade [Common (>= 1/100 to <1/10)] which were common when sub-optimal doses
of sugammadex were administered below the recommended doses.

Hypersensitivity reactions, including anaphylaxis, have been observed with
sugammadex. In a study in healthy conscious volunteers (Trial P06042; placebo,
n=150; 4 mg/kg, n=148; and 16 mg/kg, n=150), hypersensitivity reactions were
reported commonly with sugammadex 16 mg/kg (n=7, 4.7%) and uncommonly with
sugammadex 4 mg/kg (n=1, 0.7%) and none with placebo (n=0, 0%). Moreover, in
clinical trials of surgical patients hypersensitivity reactions were reported
uncommonly and for post-marketing reports, which include nonserious cases of
hypersensitivity reactions and rare serious cases describing anaphylactic
reactions, the frequency is unknown.

With respect to the effect of sugammadex on hemostasis, in a clinical study of
healthy subjects (Trial 19.4.115), doses of 4 mg.kg-1 and 16 mg.kg-1 of
sugammadex resulted in maximum mean prolongations of activated partial
thromboplastin time (aPTT) by 17 and 22% respectively and of prothrombin time
(PT) by 11 and 22% respectively. These limited, mean aPTT and PT prolongations
resolved quickly (i.e., <= 30 minutes), and pooled analysis of the Phase II/III
data from the sugammadex development program did not indicate an increase in
clinically meaningful events of bleeding. However, to further
investigate the potential clinical relevance of the observed effects on aPTT
and PT, the current study will investigate the effects of (1) reversal of
neuromuscular blockade using sugammadex at the clinical dose of 4 mg.kg-1 and
(2) reversal of neuromuscular blockade according to usual care (neostigmine or
spontaneous reversal) on adjudicated events of bleeding and coagulation
parameters in surgical patients at increased risk for bleeding events due to
concomitant administration of thromboprophylactic therapy.

The background risk associated with events of unanticipated post-surgical
bleeding varies depending on factors such as surgical procedure and concomitant
medication as well as intrinsic factors/underlying medical conditions (eg,
hemophilia, congenital platelet disorder, von Willebrand disease, advanced
hepatic insufficiency, or severe renal insufficiency). In order to better
understand the risk for bleeding in the context of previously defined
incidences of bleeding events in surgical patients, this study will assess
adult surgical patients of ASA Class 1-3 undergoing hip fracture surgery or
joint (hip/knee) replacement surgery and receiving pre- or intra-operative
thromboprophylaxis. Key features of the population of patients undergoing hip
fracture surgery or joint (hip/knee) replacement surgery and the rationale
supporting focused study of this population are listed below.

This is an appropriate population to study for a number of reasons. First,
thromboprophylactic therapies are routinely indicated in such patients because
of the high risk (40-60% without prophylaxis) of venous thromboembolism
associated with major orthopedic surgery of the lower limb. Second, focusing on
this particular set of procedures which has an increased incidence of
bleeding/blood loss may decrease the observed variability of bleeding risk
related to surgical procedure or technique while regarding the incidences of
bleeding events in patients whose neuromuscular blockade is reversed with
sugammadex versus according to usual care (neostigmine or spontaneous
reversal). Third, these procedures have well-studied risks for bleeding that
can provide historical context for incidences of bleeding events; indeed, the
best-studied paradigms assessing risk for postoperative bleeding are the
double-blind, randomized controlled thromboprophylaxis studies of hip and knee
surgeries.

An analysis of the clinical data from the pooled Phase II/III development
program for events of bleeding in patients taking antithrombotic therapy did
not demonstrate an increased risk for clinically meaningful events of bleeding.
The current study is designed to gather additional data in a prospective manner
to evaluate possible interactions manifested as clinical events in a surgical
population. To that end, this study will enrich for this population,
specifically assessing the potential of sugammadex to increase bleeding risk in
patients receiving prophylactic antithrombotic therapy.