Comparison of 2.0 mg/kg Sugammadex and Neostigmine at Reappearance of T2 in Chinese and European Subjects (Study 19.4.324)(P05768AM1)(COMPLETED)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00825812
• Collaborator: (none)
• Enrollment: 308
• Arms: 4
• Duration (Months): 8

Study Details

Study Description

Brief Summary

The present trial was set up to evaluate the efficacy and safety of 2.0 mg.kg-1 sugammadex compared to neostigmine administered at reappearance of T2 in Chinese and Caucasian subjects for registration purposes in China.

Condition or Disease	Intervention/Treatment	Phase
Anesthesia, General; Neuromuscular Blockade	Drug: Sugammadex; Drug: neostigmine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 308 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Randomized, Parallel-group, Active-controlled, Safety-assessor Blinded Trial, Comparing the Efficacy and Safety of 2.0 mg.Kg-1 Sugammadex With 50 μg.Kg-1 Neostigmine Administered at Reappearance of T2 After Rocuronium in Chinese and European ASA I-III Subjects Undergoing Elective Surgery Under Propofol Anesthesia
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sugammadex in Caucasian Subjects At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	Drug: Sugammadex; After induction of anesthesia an intubation dose of 0.6 mg/kg rocuronium was administered. Maintenance doses of 0.1-0.2 mg/kg rocuronium intravenous (IV) could be administered if necessary. At reappearance of T2 after the last administration of rocuronium, an IV single bolus dose of 2.0 mg/kg sugammadex was administered.; Other Names: Org 25969, Bridion®
Active Comparator: Neostigmine in Caucasian Subjects At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.	Drug: neostigmine; After induction of anesthesia an intubation dose of 0.6 mg/kg rocuronium was administered. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV could be administered if necessary. At reappearance of T2 after the last administration of rocuronium, an IV single bolus dose of 50 µg/kg neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.; Other Names: Neostigmine with atropine
Experimental: Sugammadex in Chinese Subjects At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	Drug: Sugammadex; After induction of anesthesia an intubation dose of 0.6 mg/kg rocuronium was administered. Maintenance doses of 0.1-0.2 mg/kg rocuronium intravenous (IV) could be administered if necessary. At reappearance of T2 after the last administration of rocuronium, an IV single bolus dose of 2.0 mg/kg sugammadex was administered.; Other Names: Org 25969, Bridion®
Active Comparator: Neostigmine in Chinese Subjects At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.	Drug: neostigmine; After induction of anesthesia an intubation dose of 0.6 mg/kg rocuronium was administered. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV could be administered if necessary. At reappearance of T2 after the last administration of rocuronium, an IV single bolus dose of 50 µg/kg neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.; Other Names: Neostigmine with atropine

Outcome Measures

Primary Outcome Measures

1. Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the T4/T1 Ratio to 0.9. [start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade]

   Neuromuscular functioning was monitored by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation was to continue until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached >= 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery. The primary analysis was the comparison between sugammadex & neostigmine among Chinese subjects; other comparisons were secondary.

Secondary Outcome Measures

1. Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8. [start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade]

   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. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

-Subjects who are willing to provide informed consent; be between 18 and 64 years old; are American Society of Anaesthesiology (ASA) class 1-3 (extremes included); scheduled for elective surgery under general anesthesia, allowing stable neuromuscular monitoring, which requires neuromuscular blockade using rocuronium; be compliant with the dose/visit schedules, and use an accepted method of contraception (if applicable).

For China only: Subjects of Chinese descent born in China, never emigrated out of China and have a Chinese home address. For Europe only: Subjects of Caucasian descent born in Europe, never emigrated out of Europe and have a European home address.

Exclusion Criteria:

-Subjects with expected difficult intubation, neuromuscular disorders affecting neuromuscular blockade, significant renal/hepatic dysfunction, use of a tourniquet, (family) history of malignant hyperthermia, allergy to general anesthesia medications, contraindication to study drugs, breast feeding, pregnant, participation in previous or new trials, a clinically significant condition that may interfere with the trial, or membership in the (family of) study/sponsor staff.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00825812
• Other Study ID Numbers: P05768; 19.4.324
• First Posted: Jan 21, 2009
• Last Update Posted: Nov 1, 2015
• Last Verified: Oct 1, 2015

• Additional relevant MeSH terms: Atropine; Neostigmine

Study Results

Participant Flow

Pre-assignment Detail	308 participants were randomized

Arm/Group Title	Sugammadex in Caucasian Subjects	Neostigmine in Caucasian Subjects	Sugammadex in Chinese Subjects	Neostigmine in Chinese Subjects
Arm/Group Description	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.
Period Title: Overall Study
STARTED	29	32	126	121
TREATED	29	31	120	111
COMPLETED	29	31	120	111
NOT COMPLETED	0	1	6	10

Baseline Characteristics

Arm/Group Title	Sugammadex in Caucasian Subjects	Neostigmine in Caucasian Subjects	Sugammadex in Chinese Subjects	Neostigmine in Chinese Subjects	Total
Arm/Group Description	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.	Total of all reporting groups
Overall Participants	29	31	120	111	291
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	52.0 (10.3)	51.9 (7.3)	39.9 (10.8)	39.4 (10.8)	42.2
Sex: Female, Male (Count of Participants)
Female	25 86.2%	28 90.3%	78 65%	86 77.5%	217 74.6%
Male	4 13.8%	3 9.7%	42 35%	25 22.5%	74 25.4%

Outcome Measures

1. Primary Outcome

Title	Time From Start of Administration of Investigational Medicinal Product (IMP) to Recovery of the T4/T1 Ratio to 0.9.
Description	Neuromuscular functioning was monitored by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing twitch response at the adductor pollicis muscle. Nerve stimulation was to continue until the ratio of the magnitude of the fourth twitch (T4) to first twitch (T1) reached >= 0.9. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade, with a value of 1.0 representing full recovery. The primary analysis was the comparison between sugammadex & neostigmine among Chinese subjects; other comparisons were secondary.
Time Frame	start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) population included all subjects who received randomized treatment and had at least one efficacy measurement. In the event of missing data, imputed data were used for analysis. 291 subjects received IMP, of whom two had no efficacy measurements at all. Hence the FAS consisted of 289 subjects.

Arm/Group Title	Sugammadex in Caucasian Subjects	Neostigmine in Caucasian Subjects	Sugammadex in Chinese Subjects	Neostigmine in Chinese Subjects
Arm/Group Description	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.
Measure Participants	29	30	119	111
Geometric Mean (95% Confidence Interval) [minutes]	1.4	6.7	1.6	9.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sugammadex in Chinese Subjects, Neostigmine in Chinese Subjects
	Comments	The primary analysis was the comparison of the two treatments among Chinese subjects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of geometric mean time to recovery
	Estimated Value	5.7
	Confidence Interval	() 95%; 4.9 to 6.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of time to recovery of 0.9 T4/T1 ratio (neostigmine time / sugammadex time).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sugammadex in Caucasian Subjects, Neostigmine in Caucasian Subjects
	Comments	A key secondary analysis was the comparison of the two treatments among Caucasian subjects.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of geometric mean time to recovery
	Estimated Value	4.8
	Confidence Interval	() 97.5%; 3.7 to 6.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of time to recovery of 0.9 T4/T1 ratio (neostigmine time / sugammadex time).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sugammadex in Caucasian Subjects, Sugammadex in Chinese Subjects
	Comments	A key secondary analysis was the comparison for equivalence between Chinese subjects and Caucasian subjects.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Equivalence was considered if the 97.5% confidence interval (CI) for median difference in recovery time (T4/T1 ratio to 0.9) was within the pre-specified range of -60 to +60 seconds.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	median difference (seconds)
	Estimated Value	7
	Confidence Interval	() 97.5%; -5 to 21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated median difference (Chinese - Caucasian) in seconds for the time to recovery of the T4/T1 ratio to 0.9 (after sugammadex).

2. Secondary Outcome

Title	Time From Start of Administration of IMP to Recovery of the T4/T1 Ratio to 0.7 and 0.8.
Description	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. The greater the T4/T1 ratio the greater the recovery from neuromuscular blockade.
Time Frame	start of administration of sugammadex/neostigmine to recovery from neuromuscular blockade

Outcome Measure Data

Analysis Population Description

The Full Analysis Set population included all subjects who received randomized treatment and had at least one efficacy measurement. In the event of missing data, imputed data were used for analysis.

Arm/Group Title	Sugammadex in Caucasian Subjects	Neostigmine in Caucasian Subjects	Sugammadex in Chinese Subjects	Neostigmine in Chinese Subjects
Arm/Group Description	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.	At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.
Measure Participants	29	30	119	111
Recovery of T4/T1 ratio to 0.7	1.0	3.4	1.1	4.4
Recovery of T4/T1 ratio to 0.8	1.2	4.6	1.3	6.0

Adverse Events

Arm/Group Title	Sugammadex in Caucasian Subjects		Neostigmine in Caucasian Subjects		Sugammadex in Chinese Subjects		Neostigmine in Chinese Subjects
Arm/Group Description	At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.		At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.		At reappearance of T2 after the last dose of rocuronium, 2.0 mg.kg-1 sugammadex was administered.		At reappearance of T2 after the last dose of rocuronium, 50 μg.kg-1 neostigmine (combined with 10-20 μg.kg-1 atropine, in a ratio ranging from 2.5:1 to 5:1) was administered.
All Cause Mortality
	Sugammadex in Caucasian Subjects		Neostigmine in Caucasian Subjects		Sugammadex in Chinese Subjects		Neostigmine in Chinese Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sugammadex in Caucasian Subjects		Neostigmine in Caucasian Subjects		Sugammadex in Chinese Subjects		Neostigmine in Chinese Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		2/31 (6.5%)		0/120 (0%)		1/111 (0.9%)
Infections and infestations
Enterococcal bacteraemia	0/29 (0%)	0	1/31 (3.2%)	1	0/120 (0%)	0	0/111 (0%)	0
Injury, poisoning and procedural complications
Anastomotic leak	0/29 (0%)	0	1/31 (3.2%)	1	0/120 (0%)	0	0/111 (0%)	0
Incision site haemorrhage	0/29 (0%)	0	0/31 (0%)	0	0/120 (0%)	0	1/111 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Sugammadex in Caucasian Subjects		Neostigmine in Caucasian Subjects		Sugammadex in Chinese Subjects		Neostigmine in Chinese Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/29 (62.1%)		26/31 (83.9%)		73/120 (60.8%)		84/111 (75.7%)
Gastrointestinal disorders
Abdominal pain	1/29 (3.4%)	2	1/31 (3.2%)	1	1/120 (0.8%)	1	6/111 (5.4%)	6
Abdominal pain upper	0/29 (0%)	0	2/31 (6.5%)	2	6/120 (5%)	6	2/111 (1.8%)	2
Nausea	4/29 (13.8%)	4	7/31 (22.6%)	9	10/120 (8.3%)	11	13/111 (11.7%)	13
Vomiting	0/29 (0%)	0	0/31 (0%)	0	11/120 (9.2%)	11	11/111 (9.9%)	11
General disorders
Fatigue	2/29 (6.9%)	2	0/31 (0%)	0	0/120 (0%)	0	0/111 (0%)	0
Pyrexia	2/29 (6.9%)	2	1/31 (3.2%)	1	16/120 (13.3%)	17	16/111 (14.4%)	16
Sensation of foreign body	0/29 (0%)	0	0/31 (0%)	0	8/120 (6.7%)	8	4/111 (3.6%)	4
Injury, poisoning and procedural complications
Anaesthetic complication cardiac	0/29 (0%)	0	5/31 (16.1%)	5	1/120 (0.8%)	2	7/111 (6.3%)	7
Incision site pain	0/29 (0%)	0	0/31 (0%)	0	28/120 (23.3%)	28	26/111 (23.4%)	26
Procedural hypotension	6/29 (20.7%)	8	14/31 (45.2%)	20	1/120 (0.8%)	1	0/111 (0%)	0
Procedural nausea	0/29 (0%)	0	0/31 (0%)	0	4/120 (3.3%)	4	7/111 (6.3%)	7
Procedural pain	13/29 (44.8%)	20	12/31 (38.7%)	15	10/120 (8.3%)	10	10/111 (9%)	10
Procedural vomiting	0/29 (0%)	0	0/31 (0%)	0	4/120 (3.3%)	4	7/111 (6.3%)	7
Wound complication	3/29 (10.3%)	3	3/31 (9.7%)	4	3/120 (2.5%)	3	2/111 (1.8%)	2
Nervous system disorders
Dizziness	2/29 (6.9%)	2	0/31 (0%)	0	11/120 (9.2%)	11	22/111 (19.8%)	23
Headache	1/29 (3.4%)	1	2/31 (6.5%)	2	5/120 (4.2%)	5	6/111 (5.4%)	6
Psychiatric disorders
Insomnia	2/29 (6.9%)	2	3/31 (9.7%)	3	2/120 (1.7%)	2	1/111 (0.9%)	1
Reproductive system and breast disorders
Vaginal haemorrhage	0/29 (0%)	0	0/31 (0%)	0	5/120 (4.2%)	5	9/111 (8.1%)	9
Respiratory, thoracic and mediastinal disorders
Increased upper airway secretion	0/29 (0%)	0	0/31 (0%)	0	5/120 (4.2%)	5	10/111 (9%)	10
Surgical and medical procedures
Hypotensive anaesthesia procedure	1/29 (3.4%)	1	2/31 (6.5%)	2	0/120 (0%)	0	0/111 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI must not publish/publicly present any interim results without prior written consent of sponsor. The PI must provide copies of material for sponsor to review, 45 days prior to submission for publication/presentation. The sponsor may review/comment. If the parties disagree on the appropriateness of the data analysis and presentation, the PI must agree to meet prior to submission for publication/presentation to make good faith efforts to discuss and resolve any issues or disagreement.