Efficacy and Safety of Org 25969 Administered After Zemuron® (MK-8616-042)

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to explore the dose-response relation of MK-8616 (Org 25969) given as a reversal agent of Zemuron® at 1 to 2 post tetanic counts (PTCs); both Zemuron® and MK-8616 are administered by intravenous (iv) infusion. Another goal of the study is to evaluate the safety of single doses of MK-8616 administered to participants of American Society of Anesthesiologists (ASA) Physical Status Class 1 (otherwise normal, healthy participant); Class 2 (participant with a mild systemic disease); or Class 3 (participant with a severe systemic disease that limits activity, but is not incapacitating).

Official Title
-----------------
A Multi-center, Randomized, Assessor-blinded, Phase II, Parallel Dose-finding Trial in Subjects of ASA Class 1 - 3 to Assess the Efficacy and Safety of 5 Doses of Org 25969 When Administered at 1-2 PTCs After Administration of Zemuron®

Conditions
-----------------
Neuromuscular Blockade

Intervention / Treatment
-----------------
* Drug: MK-8616
* Drug: Zemuron®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has an ASA Class of 1 to 3 Is scheduled for surgical procedures (excluding dental and neck surgeries) with an anticipated duration of anesthesia of ≥45 minutes with the use of Zemuron® Exclusion Criteria: Is undergoing dental or neck surgery Has anatomical malformation that would impede intubation Has or is suspected to have neuromuscular disorders impairing neuromuscular block and/or significant renal 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 medications used during general anesthesia Is pregnant Is a female of childbearing potential not using 1 of the following methods of birth control: condom or diaphragm with spermicide, vasectomized partner (<6 months), intrauterine device (IUD), or abstinence Is breast-feeding Has already participated in the study Has participated in another clinical trial, not pre-approved by Organon Pharmaceuticals USA within 30 days of entering this study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1) Zemuron® 0.6 mg/kg + MK-8616 0.5 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 0.5 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced neuromuscular blockade (NMB) reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 2) Zemuron® 1.2 mg/kg + MK-8616 0.5 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 0.5 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 3) Zemuron® 0.6 mg/kg + MK-8616 1.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 1.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 4) Zemuron® 1.2 mg/kg + MK-8616 1.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 1.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 5) Zemuron® 0.6 mg/kg + MK-8616 2.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 2.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 6) Zemuron® 1.2 mg/kg + MK-8616 2.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 2.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 7) Zemuron® 0.6 mg/kg + MK-8616 4.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 4.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 8) Zemuron® 1.2 mg/kg + MK-8616 4.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 4.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 9) Zemuron® 0.6 mg/kg + MK-8616 8.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 0.6 mg/kg followed by MK-8616 8.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|
| Experimental: 10) Zemuron® 1.2 mg/kg + MK-8616 8.0 mg/kg<br>Participants (ASA Class 1 to 3) will receive an iv bolus of Zemuron® 1.2 mg/kg followed by MK-8616 8.0 mg/kg iv during a single study session. MK-8616 will be administered once Zemuron®-induced NMB reaches 1 to 2 PTCs. | Drug: MK-8616<br>* MK-8616 will be administered at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg/kg iv as a 30-second infusion. Doses are based on actual body weight.<br>* Other names: Org 25969, sugammadex, Bridion®;Drug: Zemuron®<br>* Zemuron® (0.6 or 1.2 mg/kg, iv) will be administered as a 10-second bolus infusion to achieve 1 to 2 PTCs. If needed, a maintenance dose of 0.15 mg/kg will be given. Doses are based on actual body weight.<br>* Other names: Rocuronium bromide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Start of Administration of MK-8616 to Recovery T4/T1 Ratio to 0.9 | The mean time from the start of MK-8616 administration to recovery T4/T1 ratio of 0.9 was determined. Less time indicates faster recovery from NMB. The ratio of T4 (fourth twitch; amplitude of fourth response to train of four [TOF] stimulation is expressed as percent of control T4) over T1 (first twitch; amplitude of first response to TOF stimulation is expressed as percent of control T1) ranges from 0 (complete loss of T4 twitch response) to 1.0 (complete recovery of T4 twitch response). For TOF stimulation, 4 consecutive square wave supra-maximal stimuli of 0.2 msec duration were delivered at 2 Hz every 15 seconds. Neuromuscular monitoring was performed with the TOF-Watch® SX. | Up to 90 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing ≥1 Adverse Events (AEs) | The percentage of participants experiencing ≥1 AEs was determined. An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. | Up to 7 days following MK-8616 administration |