Dialysis of Sugammadex in Participants With Severe Renal Impairment (Study 19.4.333) (P05773)

Study Overview
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Brief Summary
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The clinical trial objectives were to evaluate the dialysability of the sugammadex-rocuronium complex; it's safety and efficacy in participants with severe renal impairment.

Detailed Description
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The current trial was designed to evaluate the dialysability of the sugammadex-rocuronium complex in participants with severe renal impairment. A dose of 4.0 mg/kg sugammadex was administered 15 minutes after administration of 0.6 mg/kg rocuronium. Blood and dialysate samples were collected before, during and after hemodialysis/filtration, for calculation of clearance of sugammadex-rocuronium complex and assessment of rebound.

Official Title
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A Single Center, Open-Label Trial in Subjects With Severe Renal Impairment Evaluating the Dialysability of the Sugammadex-Rocuronium Complex

Conditions
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Neuromuscular Blockade

Intervention / Treatment
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* Drug: sugammadex
* Drug: Rocuronium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age American Society of Anesthesiologists (ASA) Class >=4 Creatinine clearance (CLCR) < 30 mL/min and clinical indication for dialysis Hospitalization at Intensive Care Unit (ICU) and scheduled for a (surgical) procedure under general anesthesia requiring neuromuscular relaxation with the use of rocuronium Scheduled for a (surgical) procedure in supine position Written informed consent (of the legal representative) Exclusion Criteria: Known or suspected to have neuromuscular disorders impairing neuromuscular blockade and/or significant hepatic dysfunction Known or suspected to have a (family) history of malignant hyperthermia Known or suspected to have an allergy to narcotics, muscle relaxants or other medication used during general anesthesia Have already participated in a sugammadex trial Have participated in another clinical trial, not preapproved by NV Organon, within 30 days of study entry Females who are pregnant* Females who are breast-feeding * In females pregnancy will be excluded both from medical history and by a human chorionic gonadotropin (hCG) test within 24 hours before surgery except in females who are not of childbearing potential, i.e. at least 2 years menopausal or have undergone tubal ligation or an hysterectomy.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sugammadex<br>IV single bolus dose of 4.0 mg/kg sugammadex | Drug: sugammadex<br>* At 15 minutes after administration of rocuronium, an IV single bolus dose of 4.0 mg/kg sugammadex was administered.<br>* Other names: Bridion®;Drug: Rocuronium<br>* After achieving stable anesthesia an IV single bolus dose of 0.6 mg/kg rocuronium was administered<br>* Other names: Esmeron®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance of Sugammadex by Dialysis as Measured by the Reduction Ratio (RR) | Starting on Day 1 dialysis was performed on four separate occasions using a Fresenius 40008H hemodialyzer, with a hemodiafilter standard helixone membrane FX 600. Dialysate samples were collected before, and after hemodialysis, with concentrations of sugammadex determined using a liquid chromatographic assay with mass spectrometric detection. The clearance of sugammadex at each dialysis session was calculated by measuring the ratio of plasma concentration at the end of dialysis, average duration of 6 hours, compared with that immediately before the start of dialysis, called the RR. | Up to day 7 | 
| Clearance of Rocuronium by Dialysis as Measured by the Reduction Ratio (RR) | Starting on Day 1 dialysis was performed on four separate occasions using a Fresenius 40008H hemodialyzer, with a hemodiafilter standard helixone membrane FX 600. Dialysate samples were collected before, and after hemodialysis, with concentrations of rocuronium determined using a liquid chromatographic assay with mass spectrometric detection. The clearance of rocuronium at each dialysis session was calculated by measuring the ratio of plasma concentration at the end of dialysis, average duration of 6 hours, compared with that immediately before the start of dialysis, called the RR. | Up to Day 7 | 
| Rate of Clearance of Sugammadex From Blood | Starting on Day 1 dialysis was performed on four separate occasions using a Fresenius 40008H hemodialyzer, with a hemodiafilter standard helixone membrane FX 600. Blood samples were collected from ports in the arterial and venous tubing of the dialyzer before, during and after an average of 6 hours of hemodialysis. The concentrations of sugammadex were determined using a liquid chromatographic assay with mass spectrometric detection. The clearance rate from blood at each dialysis session was assessed by averaging across all available collection time points. | Up to day 7 | 
| Rate of Clearance of Rocuronium From Blood | Starting on Day 1 dialysis was performed on four separate occasions using a Fresenius 40008H hemodialyzer, with a hemodiafilter standard helixone membrane FX 600. Blood samples were collected from ports in the arterial and venous tubing of the dialyzer before, during and after an average of 6 hours of hemodialysis. The concentrations of rocuronium were determined using a liquid chromatographic assay with mass spectrometric detection. The clearance rate from blood at each dialysis session was assessed by averaging across all available collection time points. | Up to Day 7 | 
| Rate of Clearance of Sugammadex From Dialysate | Starting on Day 1 dialysis was performed on four separate occasions using a Fresenius 40008H hemodialyzer, with a hemodiafilter standard helixone membrane FX 600. Dialysate samples were collected from a port in the outflow of the dialyzer before, during and after an average of 6 hours of hemodialysis. The concentrations of sugammadex were determined using a liquid chromatographic assay with mass spectrometric detection. The clearance rate from dialysate at each dialysis session was assessed by averaging across all available collection time points.The data from the fourth dialysis are not presented as they were not calculable. | Up to day 7 | 
| Rate of Clearance of Rocuronium From Dialysate | Starting on Day 1 dialysis was performed on four separate occasions using a Fresenius 40008H hemodialyzer, with a hemodiafilter standard helixone membrane FX 600. Dialysate samples were collected from a port in the outflow of the dialyzer before, during and after an average of 6 hours of hemodialysis. The concentrations of rocuronium were determined using a liquid chromatographic assay with mass spectrometric detection. The clearance rate from dialysate at each dialysis session was assessed by averaging across all available collection time points. | Up to Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pre-treatment Adverse Events (AEs) | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body, whether or not related to the use of a product. | Screening up to Day 1 | 
| Number of Participants With Serious Adverse Events (SAEs) | A SAE is any untoward medical occurrence that at any dose results in the following: death, is life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or is a congenital anomaly/birth defect | Up to day 7 | 
| Number of Participants With Medical Device (Near) Incidents | A medical device (near) incident is defined as an occurrence due to inaccurate or inadequate labeling/instructions, or information supplied with a medical device; or malfunction, deterioration or recall of a medical device that could lead to death or serious deterioration in health. | Up to day 7 | 
| Vital Sign: Mean Systolic Blood Pressure | Systolic blood pressure was measured at the following time points: screening, before rocuronium treatment, before sugammadex treatment, at 2, 5, 10, 20 minutes post-sugammadex treatment, and the day after surgery | Screening up to 1 day after surgery | 
| Vital Sign: Mean Diastolic Blood Pressure | Diastolic blood pressure was measured at the following time points: screening, before rocuronium treatment, before sugammadex treatment, at 2, 5, 10, 20 minutes post-sugammadex treatment, and the day after surgery | Screening up to 1 day after surgery | 
| Vital Sign: Mean Heart Rate | Heart rate was measured at the following time points: screening, before rocuronium treatment, before sugammadex treatment, at 2, 5, 10, 20 minutes post-sugammadex treatment, and the day after surgery | Screening up to 1 day after surgery | 
| Number of Participants With Physical Examinations | Physical examinations were to be conducted at screening, on Day 1 and 7 days after surgery | Screening up to day 7 | 
| Number of Participants With Reoccurrence of Neuromuscular Blockade at Day 1 | Neuromuscular function was monitored by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing the magnitudes (heights) of the first twitch (T1) and fourth twitch (T4) response at the adductor pollicis muscle with a TOF-Watch® SX. Stimulation continued until the T4/T1 ratio reached at least 0.9. Higher T4/T1 ratios represent greater recovery from neuromuscular blockade; with a value of 1.0 representing full recovery. Reoccurrence of neuromuscular blockade is defined as a decline in the T4/T1 ratio from >= 0.9 to < 0.8 in at least three consecutive measurements. | Day 1 | 
| Number of Participants With Events Due to Possible Interaction of Sugammadex With Endo-/Exogenous Compounds Other Than Rocuronium | Evidence of AEs due to possible interaction of sugammadex with endogenous compounds or with exogenous compounds other than rocuronium | Day 1 | 
| Number of Participants With Pregnancies at 30 Days Post-dose | Pregnancies reported by means of a Pregnancy Reporting Form, consist of pregnant female participants or pregnant female partners of male participants | Up to 30 days post -dose | 
| Time From Start of Administration of Sugammadex to Recovery of T4/T1 Ratio to 0.9 | Neuromuscular function was monitored by applying repetitive train of four (TOF) electrical stimulations to the ulnar nerve every 15 seconds and assessing the magnitudes (heights) of the first twitch (T1) and fourth twitch (T4) response at the adductor pollicis muscle with a TOF-Watch® SX. Stimulation continued until the T4/T1 ratio reached at least 0.9. Higher T4/T1 ratios represent greater recovery from neuromuscular blockade; with a value of 1.0 representing full recovery. | Day 1 | 
| Time From Start of Administration of Sugammadex to Recovery of T4/T1 Ratio to 0.8 | Neuromuscular function was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds and assessing the magnitudes (heights) of the T1 and T4 response at the adductor pollicis muscle with a TOF-Watch® SX. Stimulation continued until the T4/T1 ratio reached at least 0.8. Higher T4/T1 ratios represent greater recovery from neuromuscular blockade; with a value of 1.0 representing full recovery. | Day 1 | 
| Time From Start of Administration of Sugammadex to Recovery of T4/T1 Ratio to 0.7 | Neuromuscular function was monitored by applying repetitive TOF electrical stimulations to the ulnar nerve every 15 seconds and assessing the magnitudes (heights) of the T1 and T4 response at the adductor pollicis muscle with a TOF-Watch® SX. Stimulation continued until the T4/T1 ratio reached at least 0.7. Higher T4/T1 ratios represent greater recovery from neuromuscular blockade; with a value of 1.0 representing full recovery. | Day 1 |