A Bridging Trial Comparing Sugammadex (Org 25969) at Reappearance of T2 in Japanese and Caucasian Participants. Part A: Japanese Participants (P05956)

Study Overview
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Brief Summary
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The objective of this trial was to establish the dose-response of T2 (the amplitude of the first response of second twitch to train of four (TOF) stimulation, expressed as percentage of control first twitch,T1) in Japanese and Caucasian participants. Part A: Japanese Participants

Detailed Description
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For most surgical procedures a depth of neuromuscular block of 1-2 twitches after TOF-stimulation is sufficient to avoid unwanted muscular activity. At reappearance of T2, the anesthesiologist might decide to either give (another) maintenance dose of rocuronium or vecuronium when surgery continues, to await spontaneous recovery of neuromuscular block or to reverse the neuromuscular block. Sugammadex (Org 25969) has been shown in previous trials to greatly reduce the time to full recovery when administered at reappearance of T2, both after rocuronium- and vecuronium-induced neuromuscular blockade. The current trial P05956 was conducted in Japan and set up to establish the dose-response relationship of sugammadex given during sevoflurane anesthesia at reappearance of T2 after rocuronium or vecuronium in Japanese participants. In addition to recovery time, also pharmacokinetics and safety of sugammadex were evaluated.

Official Title
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A Multi-Center, Randomized, Open-Label, Prospective Bridging, Parallel Dose-Finding Trial Comparing Efficacy, Safety and Pharmacokinetics of 4 Doses of Org 25969 and Placebo Administered at Reappearance of T2 After Rocuronium or Vecuronium in Japanese and Caucasian Subjects. Part A: Japanese Subjects

Conditions
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Anesthesia, General

Intervention / Treatment
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* Drug: sugammadex
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is of American Society of Anesthesiologists (ASA) class 1 - 3; Is at least 20 years but under 65 years of age; Japanese participants; Is scheduled for elective surgery in supine position and under sevoflurane anesthesia, in need of administration of neuromuscular blocking agents (NMBAs), with an anticipated duration of about 1.5-3 hours; Has given written informed consent. Exclusion Criteria: Participants in whom a difficult intubation because of anatomical malformations was expected; Is known or suspected to have neuromuscular disorders impairing the effect of NMBAs and/or significant renal dysfunction (for example a creatinine level > 1.6 mg/dl) and/or severe hepatic dysfunction. Is known or suspected to have a (family) history of malignant hyperthermia; Is known or suspected to have an allergy to narcotics, muscle relaxants or other medication used during general anesthesia; Is receiving medication expected to interfere with the rocuronium or vecuronium given in this trial, based on the dose and time of administration; Females who were pregnant; Females not using birth control or using only oral contraception as birth control continuously; Were breast-feeding; Has already participated in P05956, or in another trial with sugammadex; Has participated in another clinical trial within 6 months of entering into P05956

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Rocuronium + Placebo<br>After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered intravenously (IV), followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of placebo was administered IV. | Drug: Placebo<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of placebo IV was administered<br>|
| Experimental: Rocuronium + 0.5 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 0.5 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|
| Experimental: Rocuronium + 1.0 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 1.0 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|
| Experimental: Rocuronium + 2.0 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 2.0 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|
| Experimental: Rocuronium + 4.0 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.9 mg/kg rocuronium was administered IV, followed by maintenance doses of 0.1-0.2 mg/kg rocuronium IV if necessary. At reappearance of T2 a single dose of 4.0 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|
| Placebo Comparator: Vecuronium + Placebo<br>After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.04 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of placebo was administered IV. | Drug: Placebo<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of placebo IV was administered<br>|
| Experimental: Vecuronium + 0.5 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.04 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 0.5 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|
| Experimental: Vecuronium + 1.0 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.04 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 1.0 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|
| Experimental: Vecuronium + 2.0 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.04 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 2.0 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|
| Experimental: Vecuronium + 4.0 mg/kg sugammadex<br>After induction of anesthesia an intubation dose of 0.1 mg/kg vecuronium was administered IV, followed by maintenance doses of 0.02-0.04 mg/kg vecuronium IV if necessary. At reappearance of T2 a single dose of 4.0 mg/kg sugammadex was administered IV. | Drug: sugammadex<br>* After induction of anesthesia an intubation dose of NMBA was administered IV: either 0.9 mg/kg rocuronium or 0.1 mg/kg vecuronium. Maintenance doses of 0.1-0.2 mg/kg rocuronium IV or 0.02-0.04 mg/kg vecuronium IV could be administered if necessary. At reappearance of T2 the randomized single dose of sugammadex (0.5 to 4 mg/kg) IV was administered.<br>* Other names: Org 25969;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Start of Administration of Sugammadex or Placebo 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 and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (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. | Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.9 (up to 24 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Start of Administration of Sugammadex or Placebo 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 and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (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 NMB. A faster time to recovery of the T4/T1 Ratio to 0.7 indicates a faster recovery from NMB. | Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.7 (up to 24 hours) | 
| Time From Start of Administration of Sugammadex or Placebo 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 and assessing twitch response at the adductor pollicis muscle. T1 and T4 refer to the amplitudes (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 NMB. A faster time to recovery of the T4/T1 Ratio to 0.8 indicates a faster recovery from NMB. | Day 1: From start of sugammadex or placebo administration to recovery of T4/T1 ratio to 0.8 (up to 24 hours) |