A Randomized Trial Evaluating the Safety Profile of Sugammadex in High Surgical Risk ASA Physical Class 3 or 4 Participants

W. Joseph Herring; Yuki Mukai; Aobo Wang; Jeannine Lutkiewicz; John F. Lombard; Li Lin; Molly Watkins; David M. Broussard; Manfred Blobner

Disclosures

BMC Anesthesiol. 2021;21(259) 

In This Article

Methods

Institutional review board committees at each site approved this randomized, active comparator-controlled, multi-site, parallel-group, double-blind safety study, conducted at 27 sites in 4 countries from December 2017 to September 2019. This study was registered on clinicaltrials.gov registry on 17/11/2017 (Study protocol 145; Clinicaltrials.gov: NCT03346057). All participants provided written, informed consent. Study protocol is provided in Supplementary Information (Additional file 1).

The physician investigators at all US sites were board- certified anesthesiologists by the American Board of Anesthesiology or certified to practice anesthesiology in the United States.[23] Participating investigators within the European Union were licensed physicians with specialties in anesthesiology in their respective countries, requiring comprehensive training meeting and/or exceeding requirements in the United States.[23] All participating investigators met Health Authority qualifications to serve as investigators in clinical trials.[23] The study was conducted in accordance with principles of Good Clinical Practice and followed the recommendations of CONSORT guidelines (Additional file 2). The following independent ethics committees were: Ethik Kommission Der Stadt Wien (Austria) for 3 sites (Sozialmedizinisches Zentrum Ost Donauspital, A.O. Krankenhaus Dornbirn, and Landeskrankenhaus Feldkirch), De Videnskabsetiske Komiteer for Region Hovedstaden (Denmark) for 4 sites (Bispebjerg og Frederiksberg Hospital, Aarhus Universitets Hospital, Rigshospitalet- The Juliane Marie Centre, and Regionshospitalet Viborg), Ethik-Kommission bei der Landesaertzekammer Baden-Württemberg (Germany), University of California Davis Medical Center Institutional Review Board (US), Western Institutional Review Board (US) for 7 sites (Temple University Hospital, Jackson Memorial Hospital, Saint Peter's University Hospital, University Banner Medical Center, Beaumont Hospital -Royal Oak, University of Alabama -Birmingham, and Jersey Shore University Medical Center), Ochsner Clinic Foundation Institutional Review Board (US), Zablocki VA Medical Center Institutional Review Board (US), Mission Health (US), Copernicus Group Independent Review Board (US) for 2 sites (Tulane University and Hermann Drive Surgical Center), University of Missouri – Columbia Institutional Review Board (US), Loma Linda University Health Institutional Review Board (US), Cleveland Clinic Institutional Review Board (US), Vanderbilt Human Research Protection Program (US), Partners Human Research Committee (US), and University of Kansas Medical Center Institutional Review Board (US). The study was conducted by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The sponsor was involved in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.

Participants included men and women 18 years or older with BMI < 40 m2/kg and ASA Physical Class 3 or 4 as determined by the investigator (independent of the BMI ≥40 kg/m2 criterion) with planned surgical procedures involving moderate or deep neuromuscular block with either rocuronium or vecuronium.[22] Exclusion criteria were: pacemaker or implantable cardioverter-defibrillator precluding assessment of bradycardia or arrhythmias; plan not to reverse neuromuscular block at procedure end; neuromuscular disorder affecting neuromuscular block or assessments; severe renal insufficiency (defined as calculated CrCl < 30 mL/min by Cockroft-Gault); history or family history of malignant hyperthermia; known or suspected allergy to peri-operative medications; toremifene application within 24 h (before or after) study drug administration; pregnant, attempting to become pregnant, or lactating.

The trial consisted of four visits (Figure 1): screening visit, peri-anesthetic visit, post-anesthetic visit, and a follow-up safety contact occurring 14 days post study medication. The investigator specified the intended use of rocuronium and vecuronium as appropriate for the type of surgery (provided both strata remained open) at enrollment. The protocol did not specify anesthetic agents for induction or maintenance. Depending on treatment assignment, participants were maintained, according to standard clinical practice, in either moderate neuromuscular block (targeting train-of-four counts between 1 and 3) or deep neuromuscular block (targeting post-tetanic counts < 5) intraoperatively until the time of reversal. Neuromuscular monitoring was performed either qualitatively or quantitatively using any available technique depending on the standard of the respective study center.

Figure 1.

Description of (A) study design and (B) randomization scheme a Participants were also stratified by neuromuscular blocking agent, rocuronium or vecuronium

An automated Interactive Voice Response System was used for randomization. Treatment assignment determined the depth of neuromuscular block and study medication for its reversal, randomized among seven maintenance/reversal combinations, stratified by choice of rocuronium or vecuronium (Figure 2). Vecuronium enrollment was capped at 30% and the target number of randomized participants in the ASA Physical Class 4 stratum was approximately 25%. Within the rocuronium stratum, participants were randomized to one of four treatment groups in a 2:1:2:2 ratio as follows (N = ~ 231): 1) Moderate neuromuscular block and reversal with sugammadex 2 mg/kg; 2) Moderate neuromuscular block and reversal with neostigmine (50 μg/kg up to 5 mg maximum dose) plus glycopyrrolate (10 μg/kg up to 1 mg maximum dose) hereafter referred to as neostigmine/glycopyrrolate; 3) Deep neuromuscular block and reversal with sugammadex 4 mg/kg; 4) Deep neuromuscular block and reversal with sugammadex 16 mg/kg. Sugammadex 16 mg/kg, the dose labeled for use for reversal of high-dose rocuronium in an urgent setting, was evaluated in the context of deep block in this study.[24] Within the vecuronium stratum, participants were randomized to one of three treatment groups in a 2:1:2 ratio as follows (N = ~ 100; i.e., ~ 30% of total population): 1) Moderate neuromuscular block and reversal with sugammadex 2 mg/kg; 2) Moderate neuromuscular block and reversal with neostigmine/glycopyrrolate; 3) Deep neuromuscular block and reversal with sugammadex 4 mg/kg. Unlike rocuronium, vecuronium is not indicated for high dose use in rapid sequence induction; therefore, the vecuronium stratum contains no 16 mg/kg sugammadex arm as this dose of sugammadex is only indicated for reversal of high dose rocuronium.

Figure 2.

Participant disposition flow chart

The anesthesiologist was blinded to the reversal agent in the moderate block arms. In the deep block arms, the anesthesiologist was blinded to the dose of sugammadex. The study had a safety assessor, separate from the anesthesiologist, who was blinded to study medication assignment, depth of neuromuscular block, and drug preparation record. Induction and maintenance of anesthesia proceeded per usual practice. After the last dose of neuromuscular block, participants received the reversal agent intravenously via 2 syringes in masked fashion as a bolus within 5 min detection of reappearance of train-of-four count =2 with a lower limit of 1 and upper limit of 4 counts (in moderate block participants) or post-tetanic count of ≥1 and a train-of-four count of 0 (in deep block participants).

Study Endpoints

The primary safety outcomes compared incidences of TE arrhythmias, including sinus bradycardia, sinus tachycardia and other cardiac arrhythmias, for each of the sugammadex groups vs neostigmine/glycopyrrolate. For arrhythmia detection, continuous electrocardiogram monitoring began ≥5 min before study medication administration and lasted ≥30 min after study medication administration. An event was included in the primary analysis if it occurred within 35 min after administration of the study medication. The proportion of participants with each of the following TE arrhythmias, sustained for ≥1 min after administration of study medication, were compared: sinus bradycardia, defined as a heart rate < 60/min or any decrease by more than 20% below baseline; sinus tachycardia, defined as a heart rate ≥ 100/min or any increase by more than 20% above baseline; and other arrhythmias, defined as a new or worsened arrhythmia, e.g., atrial tachycardia or fibrillation. Pre-specified ECIs included selected non-serious and serious AEs occurring from treatment allocation/randomization through 14 days following cessation of treatment as follows: clinically relevant (CR) arrhythmias, hypersensitivity, anaphylaxis, liver transaminase elevations (i.e., aspartate aminotransferase and alanine aminotransferase ≥3-times upper limit of normal; total bilirubin ≥2-times upper limit of normal; alkaline phosphatase < 2-times upper limit of normal) and CR arrhythmias, defined as those necessitating intervention, as determined by the blinded investigator.

For this study, "treatment emergent" (TE) events refers to any of the previously defined deviations in the electrocardiogram from a regular sinus rhythm that emerged in the time period as defined, following administration of study drug (NMBA reversal agent to treat NMB). In this context, use of the word "treatment" in TE terminology refers only to NMB reversal agent study drug, and does not refer to whether treatment of any kind was carried out for TE arrhythmia events. The term TE is therefore independent of a possible treatment for the TE event itself. In this way, all TE events were objectively identified and included in the analyses of endpoints. This approach avoided subjectivity on the part of the treating physician to decide whether an event had occurred based on a clinical decision of whether or not to treat the arrhythmia event.

An external clinical adjudication committee of anesthesia and allergy experts, blinded to treatment, classified potential cases of hypersensitivity and/or anaphylaxis. The general safety profile of sugammadex also was assessed by monitoring of AEs up to 7 days post-treatment and comparing the incidences of specific AEs, by system organ classes and laboratory/vital sign values by predefined limits of changes in one or more of the treatment groups. A supplemental summary of all AEs occurring up to 14 days post administration of study medication also was provided.

Statistical Analysis

Safety analyses were based on the All Participants as Treated Population which included all randomized participants who received at least one dose of study medication. A tiered approach was applied to the safety analyses. The primary safety endpoints (i.e., proportion of participants with TE cardiac arrythmias) were subject to inferential testing for statistical significance with 95% confidence intervals for between-group comparisons. Secondary safety parameters (e.g., CR cardiac arrythmias adjudicated hypersensitivity and anaphylaxis, and some other supportive safety parameters) were assessed via point estimates with 95% confidence intervals provided for between-group comparisons; only point estimates by treatment group were provided for the remainder of the safety parameters. Between-group comparisons were performed for each dose group vs neostigmine/glycopyrrolate pooled across rocuronium and vecuronium stratum. P-value significance testing and 95% confidence intervals for between-group comparisons used the stratified Miettinen and Nurminen method with rocuronium and vecuronium and with ASA Physical Class as stratification factors and were provided to guide clinical interpretation of the results.[25] Since no adjustments were made for multiple treatment comparisons, the nominal P-values should be interpreted with caution. All statistical tests were conducted at the α = 0.05 (2-sided) level.

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