Comparison of Sugammadex With Neostigmine During Laparoscopic Cholecystectomy or Appendectomy (P05699)

Anesthesia, General Clinical Trial

Official title:

A Multi-center, Randomized, Parallel-group, Comparative, Active-controlled, Safety-assessor Blinded Trial in Adult Subjects Comparing the Efficacy and Safety of Sugammadex (SCH 900616, ORG 25969) Administered at 1-2 PTC With Neostigmine Administered at Reappearance of T2 in Subjects Undergoing Laparoscopic Cholecystectomy or Appendectomy Under Propofol Anesthesia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00724932
• Other study ID #: P05699
• Secondary ID: 19.4.318MK-8616-
• Status: Completed
• Phase: Phase 3
• First received: July 28, 2008
• Last updated: February 26, 2015
• Start date: July 2008
• Est. completion date: May 2009

Study information

• Verified date: February 2015
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Finland: Finnish Medicines AgencyGermany: Federal Institute for Drugs and Medical DevicesRussia: Ministry of Health of the Russian FederationUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The current trial was designed to demonstrate faster recovery from a neuromuscular blockade (NMB) induced by rocuronium after reversal at 1-2 Post Tetanic Count (PTC) by 4.0 mg.kg-1 sugammadex compared to 50 µg.kg-1 neostigmine at reappearance of second twitch (T2) in participants undergoing laparoscopic cholecystectomy or appendectomy under propofol anesthesia, to compare safety and to evaluate operating room and Post Anesthetic Care Unit (PACU) length of stay.

Description:

In those surgical procedures where a neuromuscular block is desired for intubation and/or avoid unwanted muscular activity, anesthesiologists may use a more profound NMB until the end of surgery, e.g. in open abdominal procedures or during laparoscopic procedures in order to improve surgical conditions. Reversal with sugammadex at a dose of 4.0 mg.kg-1 at 1-2 PTC after an intubation dose of 0.6 mg.kg-1 or maintenance dosing rocuronium has been found to be both safe and efficacious in previous clinical trials but has never been investigated exclusively in participants undergoing laparoscopic cholecystectomy or appendectomy.

With sugammadex profound muscle relaxation may now be provided right up to the end of the surgical procedure. This may lead to improved Patient Outcomes, such as improvement in the time from end of surgery to the discharge to the PACU. In this multi-center, randomized, parallel-group, active-controlled, safety-assessor blinded trial such benefits will be further investigated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: May 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants of American Society of Anesthesiologists class 1-3

• Participants of age above or equal to the age of 18 years

• Participants who are scheduled to undergo a laparoscopic cholecystectomy or appendectomy under general anesthesia requiring neuromuscular relaxation with rocuronium, and if applicable, maintenance of neuromuscular blockade

• Participants who have given written informed consent

Exclusion Criteria:

• Participants in whom a difficult intubation because of anatomical malformations is expected

• Participants known or suspected to have neuromuscular disorders affecting NMB

• Participants known or suspected to have a significant renal dysfunction

• Participants known or suspected to have a severe hepatic dysfunction

• Participants known or suspected to have (family) history of malignant hyperthermia

• Participants known or suspected to have an allergy to opioids, muscle relaxants or other medication used during general anesthesia

• Participants in whom the use of neostigmine and/or atropine is contraindicated

• Female participants who are pregnant (pregnancy will be excluded for women both from medical history and by a human chorionic gonadotropin (hCG) test within 24h before surgery, except for women who are not of childbearing potential, i.e. at least 2 years menopausal or have undergone tubal ligation or a hysterectomy)

• Female participants who are breast-feeding

• Participants who participated in another clinical trial not pre-approved by the sponsor, within 30 days of entering into trial 19.4.318 (P05699)

• Participants who have already participated in a sugammadex trial

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anesthesia, General

Intervention

Drug:
• Rocuronium
Participants will receive an intravenous (i.v.) single bolus dose of 0.6 mg.kg-1 rocuronium. After this dose, maintenance doses of 0.1-0.2 mg.kg-1 rocuronium may be given.
• Sugammadex
After the last dose of rocuronium has been administered, participants will receive, according to the randomization, a single bolus dose of 4.0 mg.kg-1 sugammadex at 1-2 PTC.
• Neostigmine
After the last dose of rocuronium has been administered, participants will receive, according to the randomization, 50 µg.kg-1 neostigmine (with atropine in a ratio of 5:1 for neostigmine:atropine) at reappearance of T2.
• Atropine
After the last dose of rocuronium has been administered, participants will receive, according to randomization, 10 µg.kg-1 atropine (with neostigmine in a ratio of 5:1 for neostigmine:atropine) at reappearance of T2.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

References & Publications (7)

Aldrete JA, Kroulik D. A postanesthetic recovery score. Anesth Analg. 1970 Nov-Dec;49(6):924-34. — View Citation

Apfel CC, Kranke P, Eberhart LH, Roos A, Roewer N. Comparison of predictive models for postoperative nausea and vomiting. Br J Anaesth. 2002 Feb;88(2):234-40. Review. — View Citation

Apfel CC, Läärä E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology. 1999 Sep;91(3):693-700. — View Citation

Caldwell JE. Reversal of residual neuromuscular block with neostigmine at one to four hours after a single intubating dose of vecuronium. Anesth Analg. 1995 Jun;80(6):1168-74. — View Citation

Geldner G, Niskanen M, Laurila P, Mizikov V, Hübler M, Beck G, Rietbergen H, Nicolayenko E. A randomised controlled trial comparing sugammadex and neostigmine at different depths of neuromuscular blockade in patients undergoing laparoscopic surgery. Anaes — View Citation

Irie T, Uekama K. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J Pharm Sci. 1997 Feb;86(2):147-62. Review. — View Citation

Suresh D, Carter JA, Whitehead JP, Goldhill DR, Flynn PJ. Cardiovascular changes at antagonism of atracurium. Effects of different doses of premixed neostigmine and glycopyrronium in a ratio of 5:1. Anaesthesia. 1991 Oct;46(10):877-80. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.5 and 0.6	Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds & assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the magnitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0). Faster times to recovery of the T4/T1 Ratios to 0.5 and 0.6 indicate faster recoveries from NMB.	From start of IMP administration to recovery of T4/T1 Ratio to 0.5 and 0.6 (ranging from ~1 minute to ~4 minutes)	No
Other	Time From Start of Administration of the Last Dose of Rocuronium to Recovery of the T4/T1 Ratio to 0.5, 0.6, 0.7, 0.8 and 0.9	Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds & assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the magnitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0). A faster time to recovery of the T4/T1 Ratio indicates a faster recovery from NMB.	From start of last dose of rocuronium to recovery of T4/T1 Ratio to 0.5, 0.6, 0.7, 0.8 and 0.9 (ranging from ~12 minutes to ~36 minutes)	No
Other	Time From Start of Administration of the Last Dose of Rocuronium to the Time of 1-2 PTC in the 4.0 mg.Kg-1 Sugammadex Group	The time of 1-2 PTC refers to when 1-2 twitches are generated after tetanic stimulation. Time to 1-2 PTC is the time point of the last single twitch >0 or baseline (in case of noise or direct stimulation) within the sequence of a PTC measurement. 1-2 PTC was the target depth of NMB at which sugammadex was to be administered.	From last dose of rocuronium to 1-2 PTC (up to ~9 minutes)	No
Other	Time From Start of Administration of the Last Dose of Rocuronium to the Time of Reappearance of T2 in the 50 µg.Kg-1 Neostigmine Group	The time of reappearance of T2 refers to when the second twitch reappears after TOF stimulation. Reappearance of T2 was the target depth of NMB at which neostigmine was to be administered.	From last dose of rocuronium to reappearance of T2 (up to ~26 minutes)	No
Other	Mean Systolic Blood Pressure	Systolic Blood Pressure was measured at screening, before start of rocuronium administration, before start of IMP administration, at 2, 5, 10, 30 minutes post-IMP administration, and at the post-anesthetic visit (the day after surgery).	At screening, pre-rocuronium, pre-IMP, at 2, 5, 10, and 30 minutes post-IMP, and at the post-anesthetic visit (the day after surgery)	Yes
Other	Mean Diastolic Blood Pressure	Diastolic Blood Pressure was measured at screening, before start of rocuronium administration, before start of IMP administration, at 2, 5, 10, 30 minutes post-IMP administration, and at the post-anesthetic visit (the day after surgery).	At screening, pre-rocuronium, pre-IMP, at 2, 5, 10, and 30 minutes post-IMP, and at the post-anesthetic visit (the day after surgery)	Yes
Other	Mean Heart Rate	Heart Rate was measured at screening, before start of rocuronium administration, before start of IMP administration, at 2, 5, 10, 30 minutes post-IMP administration, and at the post-anesthetic visit (the day after surgery).	At screening, pre-rocuronium, pre-IMP, at 2, 5, 10, and 30 minutes post-IMP, and at the post-anesthetic visit (the day after surgery)	Yes
Other	Number of Participants Who Had Physical Examinations	Physical examinations were to be conducted at screening (within 7 days prior to surgery) and at the post-anesthetic visit (the day after surgery).	At screening (within 7 days prior to surgery) and at the post-anesthetic visit (the day after surgery)	Yes
Other	Number of Participants With Train-of-Four- (TOF-) Watch® SX and Arm Board Related Adverse Events	Events were to be collected for the entire period of neuromuscular transmission monitoring and were defined as an occurrence that resulted or could have resulted in: death; a serious deterioration in the state of health of a user; an occurrence which might, if it recurred, lead to death or serious deterioration in health; inaccuracy as well as any inadequacy in the labeling or instructions which could cause misuse or incorrect maintenance or adjustment which might lead to a death or serious deterioration in health; an examination of the medical device or the information supplied with the medical device indicated some factor with the potential for an incident involving death or serious deterioration in health; malfunction or deterioration in characteristics and/or performance of a medical device, which might lead to death, or serious deterioration in health; technical/medical recalls involving risk of death or serious deterioration in the state of health of the user.	From induction of anesthesia to recovery from NMB (up to ~3 hours)	Yes
Other	Number of Participants With Reoccurrence of Neuromuscular Blockade Based on the Train-of-Four- (TOF-) Watch® SX Recording (i.e. a Decline in T4/T1 Ratio From >=0.9 to <0.8 in at Least Three Consecutive TOF Values)	Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the magnitudes (heights) of the 1st and 4th twitches, respectively, after TOF stimulation. The T4/T1 Ratio is expressed as a decimal of up to 1.0. A higher ratio indicates greater recovery from NMB. A decline in the T4/T1 ratio from >=0.9 (indicating a recovery from NMB) to <0.8 for at least three consecutive TOF values was considered to be a reoccurrence of NMB.	Up to 30 minutes after IMP administration	Yes
Other	Number of Participants With Clinical Evidence of Reoccurrence of Neuromuscular Blockade or Residual Neuromuscular Blockade (Routine Oxygen Saturation by Pulse Oximetry and Breath Frequency Measurement)	Clinical evidence of reoccurrence of NMB or residual NMB was assessed by oxygen saturation (by pulse oximetry) and breath frequency measurements as per routine practice after anesthesia and neuromuscular monitoring.	Up to 24 hours after IMP administration	Yes
Other	Number of Participants With Events Due to a Possible Interaction of Sugammadex With Endogenous Compounds or With Exogenous Compounds Other Than Rocuronium	Any evidence of events due to a possible interaction of sugammadex with endogenous compounds or with exogenous compounds other than rocuronium, was to be recorded.	Up to 7 days after IMP administration	Yes
Other	Monitoring of Clinical Signs of Recovery According to Routine Anesthetic Procedures at the Trial Sites	The monitoring of clinical signs of recovery was to be conducted based on the routine anesthetic procedures at each site.	Up to PACU discharge (up to ~4.5 hours)	Yes
Other	Number of Female Participants or Partners of Male Participants Who Became Pregnant During Study	Thirty days after administration of IMP, female participants of childbearing potential were asked whether they became pregnant during the trial and male participants were asked whether their partner (if of childbearing potential) became pregnant during the trial.	Up to 30 days after IMP administration	Yes
Other	Time From Operating Room Admission to Operating Room Discharge Ready	The time of Operating Room admission was defined as the time at which the participant was physically placed into the Operating Room. The time of Operating Room discharge ready was defined as time at which the participant had T4/T1 ratio of =0.9 and the participant's wound dressing was in place.	From Operating Room admission to Operating Room discharge ready (up to ~3 hours)	No
Other	Time From Operating Room Admission to Actual Operating Room Discharge	The time of Operating Room admission was defined as the time at which the participant was physically placed into the Operating Room. The time of Operating Room discharge was defined as the actual time the participant was discharged from the Operating Room.	From Operating Room admission to actual Operating Room discharge (up to ~3 hours)	No
Other	Time From Operating Room Discharge Ready to Actual Operating Room Discharge	The time of Operating Room discharge ready was defined as time at which the participant had T4/T1 ratio of >=0.9 and the participant's wound dressing was in place. The time of Operating Room discharge was defined as the actual time the participant was discharged from the Operating Room.	From Operating Room discharge ready to actual Operating Room discharge (up to ~5 minutes)	No
Other	Time From Start of IMP Administration to T4/T1 Ratio of <=0.60, >0.60 - <=0.70, >0.70 - <=0.80, >0.80 - <0.90 and >=0.90	The time of IMP administration was defined as the actual time at which IMP administration was started.	From start of IMP administration to recovery of the T4/T1 ratio to the designated value (ranging from ~1 minute to ~10 minutes)	No
Other	Time From Start of IMP Administration to Tracheal Extubation	The time of IMP administration was defined as the actual time at which IMP administration was started. The time of tracheal extubation was defined as the actual time at which the participant was extubated.	From start of IMP administration to tracheal extubation (up to ~21 minutes)	No
Other	Time From Start of IMP Administration to Operating Room Discharge Ready	The time of IMP administration was defined as the actual time at which IMP administration was started. The time of Operating Room discharge ready was defined as time at which the participant had T4/T1 ratio of >=0.9 and the participant's wound dressing was in place.	From start of IMP administration to Operating Room discharge ready (up to ~21 minutes)	No
Other	Time From Start of IMP Administration to Actual Operating Room Discharge	The time of IMP administration was defined as the actual time at which IMP administration was started. The time of Operating Room discharge was defined as the actual time at which the participant was discharged from the Operating Room.	From start of IMP administration to actual Operating Room discharge (up to ~26 minutes)	No
Other	Time From Tracheal Extubation to Operating Room Discharge Ready	The time of tracheal extubation was defined as the actual time at which the participant was extubated. The time of Operating Room discharge ready was defined as time at which the participant had T4/T1 ratio of >=0.9 and the participant's wound dressing was in place.	From tracheal extubation to Operating Room discharge ready (up to ~1 minute)	No
Other	Time From Tracheal Extubation to Actual Operating Room Discharge	The time of tracheal extubation was defined as the actual time at which the participant was extubated. The time of Operating Room discharge was defined as the actual time at which the participant was discharged from the Operating Room.	From tracheal extubation to actual OR discharge (up to ~5 minutes)	No
Other	Time From Operating Room Discharge Ready to Post Anesthetic Care Unit (PACU) Discharge Ready	The time of Operating Room discharge ready was defined as time at which the participant had T4/T1 ratio of >=0.9 and the participant's wound dressing was in place. The time of PACU discharge ready was defined as the time at which the participant had a Modified Aldrete Score >=9. The Modified Aldrete Score was to be assessed at PACU arrival, at 5, 15, 30, 45, 60 minutes after PACU arrival and every 15 minutes thereafter (if applicable) until the participant was ready to be discharged from the PACU. The Modified Aldrete Postoperative Recovery Score (range = 0-10) is calculated based on scores of 0 to 2 each for Activity, Respiration, Circulation, Consciousness and Oxygen Saturation, with a higher score indicating increased postoperative recovery.	From Operating Room discharge ready to PACU discharge ready (up to ~33 minutes)	No
Other	Time From Operating Room Discharge Ready to Actual PACU Discharge	The time of Operating Room discharge ready was defined as time at which the participant had T4/T1 ratio of >=0.9 and the participant's wound dressing was in place. The time of PACU discharge was defined as the actual time the participant was discharged from the PACU.	From Operating Room discharge ready to actual PACU discharge (up to ~4.5 hours)	No
Other	Time From Actual Operating Room Discharge to PACU Discharge Ready	The time of Operating Room discharge was defined as the actual time the participant was discharged from the Operating Room. The time of PACU discharge ready was defined as the time at which the participant had a Modified Aldrete Score >=9. The Modified Aldrete Score was to be assessed at PACU arrival, at 5, 15, 30, 45, 60 minutes after PACU arrival and every 15 minutes thereafter (if applicable) until the participant was ready to be discharged from the PACU. The Modified Aldrete Postoperative Recovery Score (range = 0-10) is calculated based on scores of 0 to 2 each for Activity, Respiration, Circulation, Consciousness and Oxygen Saturation, with a higher score indicating increased postoperative recovery.	From actual Operating Room discharge to PACU discharge ready (up to ~30 minutes)	No
Other	Time From Actual Operating Room Discharge to Actual PACU Discharge	The time of Operating Room discharge was defined as the actual time the participant was discharged from the Operating Room. The time of PACU discharge was defined as the actual time the participant was discharged from the PACU.	From actual Operating Room discharge to actual PACU discharge (up to ~4.4 hours)	No
Other	Time From PACU Admit to PACU Discharge Ready	The time of PACU admit was defined as the actual time the participant was admitted to the PACU. The time of PACU discharge ready was defined as the time at which the participant had a Modified Aldrete Score >=9. The Modified Aldrete Score was to be assessed at PACU arrival, at 5, 15, 30, 45, 60 minutes after PACU arrival and every 15 minutes thereafter (if applicable) until the participant was ready to be discharged from the PACU. The Modified Aldrete Postoperative Recovery Score (range = 0-10) is calculated based on scores of 0 to 2 each for Activity, Respiration, Circulation, Consciousness and Oxygen Saturation, with a higher score indicating increased postoperative recovery.	From PACU admit to PACU discharge ready (up to ~25 minutes)	No
Other	Time From PACU Admit to Actual PACU Discharge	The time of PACU admit was defined as the actual time the participant was admitted to the PACU. The time of PACU discharge was defined as the actual time the participant was discharged from the PACU.	From PACU admit to actual PACU discharge (up to ~4.3 hours)	No
Primary	Time From Start of Administration of Investigational Medicinal Product (IMP, Sugammadex or Neostigmine) to Recovery of the Fourth Twitch/First Twitch (T4/T1) Ratio to 0.9	Neuromuscular functioning was monitored by applying repetitive Train-Of-Four (TOF) electrical stimulations to the ulnar nerve every 15 seconds & assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the magnitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0) indicates the extent of recovery from neuromuscular blockade (NMB). In this study, twitch responses were recorded until the T4/T1 Ratio reached >= 0.9, the minimum acceptable ratio that indicated recovery from NMB. A faster time to recovery of the T4/T1 Ratio to 0.9 indicates a faster recovery from NMB.	From start of IMP administration to recovery of T4/T1 ratio to 0.9 (ranging from ~2 minutes to ~9 minutes)	No
Secondary	Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7	Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds & assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the magnitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0). A faster time to recovery of the T4/T1 Ratio to 0.7 indicates a faster recovery from NMB.	From start of IMP administration to recovery of T4/T1 Ratio to 0.7 (ranging from ~2 minutes to ~5 minutes)	No
Secondary	Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.8	Neuromuscular functioning was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds & assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the magnitudes (heights) of the first and fourth twitches, respectively, after TOF nerve stimulation. The T4/T1 Ratio (expressed as a decimal of up to 1.0). A faster time to recovery of the T4/T1 Ratio to 0.8 indicates a faster recovery from NMB.	From start of IMP administration to recovery of T4/T1 Ratio to 0.8 (ranging from ~2 minutes to ~6 minutes)	No
Secondary	Number of Participants Who Experienced Pre-treatment Serious Adverse Events (SAEs) and Post-treatment SAEs	An SAE is defined as any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect.; Participants were monitored for occurrence SAEs for up to 7 days after last dose IMP. Pre-treatment refers to the period from signing of the informed consent up to start of IMP administration. Post-treatment refers to the period from start of IMP administration to 7 days after IMP administration.	From signing of informed consent to end of trial (7 days after surgery)	Yes
Secondary	Number of Participants Who Experienced Pre-treatment Non-serious Adverse Events (AEs) and Post-treatment Non-serious AEs	An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body, whether or not considered related to the use of the product. Participants were monitored for occurrence AEs for up to 7 days after last dose IMP. Pre-treatment refers to the period from signing of the informed consent up to start of IMP administration. Post-treatment refers to the period from start of IMP administration to 7 days after IMP administration.	From signing of informed consent to end of trial (7 days after surgery)	Yes