Lemmens 2010.

Methods	Study design: multi‐centre, randomized, parallel‐group, safety assessor‐blinded, phase 3a trial (SIGNAL study) Sample size calculation: powered to detect a difference of 5 minutes in time to recovery of TOFR to 0.9
Participants	Number of randomized participants: 94 Inclusion criteria: adults > 18 years, ASA I to IV, scheduled to undergo elective surgery in the supine position under general anaesthesia requiring use of a neuromuscular blocking agent for tracheal intubation and maintenance of neuromuscular block Exclusion criteria: neuromuscular disorder; history of malignant hyperthermia; significant renal dysfunction; allergy to narcotics, muscle relaxants, or other medication used during general anaesthesia; using medication known to interfere with neuromuscular blocking agents (e.g. antibiotics, anticonvulsants, magnesium); or pregnant, breastfeeding, or of childbearing potential and not using an adequate method of contraception
Interventions	Anaesthesia: induced with intravenous opioid and propofol; maintained with intravenous opioid and sevoflurane NMBA: single intubating dose: vecuronium 0.1 mg/kg; maintenance dose: vecuronium 0.015 mg/kg Comparison: sugammadex 4.0 mg/kg (n = 52) vs neostigmine 70 µg/kg + 14 µg/kg glycopyrrolate (n = 42) Administration time of sugammadex or neostigmine: reappearance of PTC 1 to 2
Outcomes	Primary efficacy variable: time from start of administration of Org 25969/neostigmine to recovery T4/T1 ratio to 0.9 Secondary efficacy variables: time from start of administration of Org 25969/neostigmine to recovery T4/T1 ratio to 0.7 and 0.8; assessment of clinical signs of recovery (level of consciousness, 5 second head‐lift, general muscle weakness) Safety analysis: adverse events, serious adverse events, laboratory data, vital signs
Notes	Publication type: peer‐reviewed article Country: USA, 9 centres Handling of adverse events: Data presented in "Clinical signs of recovery" section (page 7) regarding number of participants with general muscle weakness and number not able to perform 5 second head‐lift were considered to show adverse events in this review and were counted as such Conversions: none Authors’ conclusions: Sugammadex provided effective and rapid reversal of profound neuromuscular block induced by vecuronium under sevoflurane anaesthesia Contact: first trial author Hendrikus JM Lemmens contacted by email: hlemmens@stanford.edu; replied referring to Merck, but did not supply contact email address at Merck
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Computer‐generated randomization schedule prepared centrally by the study sponsor"
Allocation concealment (selection bias)	Low risk	Central allocation (secondary to central randomization)
Blinding of participants (performance bias)	High risk	Open‐label study; no further information available
Blinding of personnel (performance bias)	High risk	Open‐label study; no further information available
Blinding of primary outcome assessment (detection bias)	High risk	Open‐label study; no further information available
Blinding of safety assessment (detection bias)	Low risk	Only safety assessor was blinded. Drugs were prepared by an investigator who was not involved in safety assessments
Incomplete outcome data (attrition bias) All outcomes	High risk	Imbalance in distribution: After interim analysis and recommendation by the Data and Safety Monitoring Board, the neostigmine group was discontinued because of marked differences in efficacy between treatments, although by this time, 42 participants had already been randomized into the neostigmine group. A total of 11 participants (5 sugammadex and 6 neostigmine) discontinued the trial before receiving the study drug. In addition, 1 participant randomized to vecuronium and sugammadex received rocuronium plus neostigmine and was excluded from the all‐subjects‐treated population, but was included in the intent‐to‐treat population according to the randomization schedule. Therefore, the all‐subjects‐treated population consisted of 46 participants treated with sugammadex and 36 treated with neostigmine, and the intent‐to‐treat population consisted of 47 participants randomized to sugammadex and 36 randomized to neostigmine
Selective reporting (reporting bias)	Low risk	Study protocol is available on clinicaltrials.gov (NCT00473694), and all of the study's prespecified outcomes of interest to the review have been reported in the prespecified way
Funding bias	High risk	Study was funded by Merck Research Laboratories, Summit, New Jersey, USA. Hendrikus Lemmens has participated in a Merck advisory board. Jovino Ben Morte is an employee of Merck Research Laboratories, Summit, New Jersey, USA. Mohammad El‐Orbany has received research funding from Merck. James Berry and Gavin Martin declare that they have no other competing interests
Other bias	High risk	Study sample size calculation designed to address this review's primary outcome. One intervention group was discontinued owing to marked differences in efficacy between groups after interim analysis