Trial Outcomes & Findings for Dialysis of Sugammadex in Participants With Severe Renal Impairment (Study 19.4.333) (P05773) (NCT NCT00656799)

NCT ID: NCT00656799

Last Updated: 2015-03-10

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 6 participants
• Primary outcome timeframe: Up to day 7
• Results posted on: 2015-03-10

Participant Flow

Participant milestones

Measure	Sugammadex Intravenous (IV) single bolus dose of 4.0 mg/kg sugammadex
Overall Study STARTED	6
Overall Study COMPLETED	4
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Measure	Sugammadex Intravenous (IV) single bolus dose of 4.0 mg/kg sugammadex
Overall Study Death	2

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Age, Continuous	76 years STANDARD_DEVIATION 7 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to day 7

Population: All subjects pharmacokinetically evaluable consisting of all participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Clearance of Sugammadex by Dialysis as Measured by the Reduction Ratio (RR) First Dialysis (n=5)	0.687 Reduction Ratio Standard Deviation 0.113
Clearance of Sugammadex by Dialysis as Measured by the Reduction Ratio (RR) Second Dialysis (n=6)	0.566 Reduction Ratio Standard Deviation 0.150
Clearance of Sugammadex by Dialysis as Measured by the Reduction Ratio (RR) Third Dialysis (n=4)	0.516 Reduction Ratio Standard Deviation 0.232
Clearance of Sugammadex by Dialysis as Measured by the Reduction Ratio (RR) Fourth Dialysis (n=4)	0.532 Reduction Ratio Standard Deviation 0.144

PRIMARY outcome

Timeframe: Up to Day 7

Population: All subjects pharmacokinetically evaluable consisting of all participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Clearance of Rocuronium by Dialysis as Measured by the Reduction Ratio (RR) First Dialysis (n=5)	0.750 Reduction Ratio Standard Deviation 0.0786
Clearance of Rocuronium by Dialysis as Measured by the Reduction Ratio (RR) Second Dialysis (n=6)	0.625 Reduction Ratio Standard Deviation 0.144
Clearance of Rocuronium by Dialysis as Measured by the Reduction Ratio (RR) Third Dialysis (n=4)	0.521 Reduction Ratio Standard Deviation 0.0489
Clearance of Rocuronium by Dialysis as Measured by the Reduction Ratio (RR) Fourth Dialysis (n=4)	0.458 Reduction Ratio Standard Deviation 0.115

PRIMARY outcome

Timeframe: Up to day 7

Population: All subjects pharmacokinetically evaluable consisting of all participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Rate of Clearance of Sugammadex From Blood Fourth Dialysis (n=4)	83.4 mL/min Standard Deviation 16.5
Rate of Clearance of Sugammadex From Blood First Dialysis (n=5)	79.1 mL/min Standard Deviation 19.0
Rate of Clearance of Sugammadex From Blood Second Dialysis (n=6)	76.5 mL/min Standard Deviation 19.6
Rate of Clearance of Sugammadex From Blood Third Dialysis (n=4)	72.4 mL/min Standard Deviation 18.4

PRIMARY outcome

Timeframe: Up to Day 7

Population: All subjects pharmacokinetically evaluable consisting of all participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Rate of Clearance of Rocuronium From Blood First Dialysis (n=5)	80.2 mL/min Standard Deviation 15.2
Rate of Clearance of Rocuronium From Blood Second Dialysis (n=6)	86.3 mL/min Standard Deviation 14.1
Rate of Clearance of Rocuronium From Blood Third Dialysis (n=4)	94.1 mL/min Standard Deviation 14.8
Rate of Clearance of Rocuronium From Blood Fourth Dialysis (n=3)	94.8 mL/min Standard Deviation 9.68

PRIMARY outcome

Timeframe: Up to day 7

Population: All subjects pharmacokinetically evaluable consisting of all participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Rate of Clearance of Sugammadex From Dialysate First Dialysis (n=5)	63.0 mL/min Standard Deviation 8.74
Rate of Clearance of Sugammadex From Dialysate Second Dialysis (n=6)	65.1 mL/min Standard Deviation 7.06
Rate of Clearance of Sugammadex From Dialysate Third Dialysis (n=4)	66.8 mL/min Standard Deviation 13.2

PRIMARY outcome

Timeframe: Up to Day 7

Population: All subjects pharmacokinetically evaluable consisting of all participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Rate of Clearance of Rocuronium From Dialysate Second Dialysis (n=6)	97.2 mL/min Standard Deviation 32.4
Rate of Clearance of Rocuronium From Dialysate First Dialysis (n=5)	75.1 mL/min Standard Deviation 5.81
Rate of Clearance of Rocuronium From Dialysate Third Dialysis (n=4)	110 mL/min Standard Deviation 36.4
Rate of Clearance of Rocuronium From Dialysate Fourth Dialysis (n=4)	95.3 mL/min Standard Deviation 19.2

SECONDARY outcome

Timeframe: Screening up to Day 1

Population: All Subjects Treated (AST) consisting of participants who received a dose of sugammadex

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Number of Participants With Pre-treatment Adverse Events (AEs)	1 participants

SECONDARY outcome

Timeframe: Up to day 7

Population: AST consisting of all participants who received a dose of sugammadex

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

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Number of Participants With Serious Adverse Events (SAEs)	2 participants

SECONDARY outcome

Timeframe: Up to day 7

Population: AST consisting of all participants who received a dose of sugammadex

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Number of Participants With Medical Device (Near) Incidents	0 participants

SECONDARY outcome

Timeframe: Screening up to 1 day after surgery

Population: AST consisting of all participants who received a dose of sugammadex

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

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Vital Sign: Mean Systolic Blood Pressure 10 minutes post-sugammadex	98.0 mm Hg Standard Deviation 10.9
Vital Sign: Mean Systolic Blood Pressure Post-anesthetic	146.3 mm Hg Standard Deviation 26.7
Vital Sign: Mean Systolic Blood Pressure Screening	124.2 mm Hg Standard Deviation 19.2
Vital Sign: Mean Systolic Blood Pressure Pre-Rocuronium	106.3 mm Hg Standard Deviation 25.2
Vital Sign: Mean Systolic Blood Pressure Baseline pre-sugammadex	105.5 mm Hg Standard Deviation 20.4
Vital Sign: Mean Systolic Blood Pressure 2 minutes post-sugammadex	105.0 mm Hg Standard Deviation 11.5
Vital Sign: Mean Systolic Blood Pressure 5 minutes post-sugammadex	103.2 mm Hg Standard Deviation 10.0
Vital Sign: Mean Systolic Blood Pressure 30 minutes post-sugammadx	92.8 mm Hg Standard Deviation 21.3

SECONDARY outcome

Timeframe: Screening up to 1 day after surgery

Population: AST consisting of all participants who received a dose of sugammadex

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

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Vital Sign: Mean Diastolic Blood Pressure 2 minutes post-sugammadex	46.5 mm Hg Standard Deviation 12.3
Vital Sign: Mean Diastolic Blood Pressure 5 minutes post-sugammadex	44.5 mm Hg Standard Deviation 12.1
Vital Sign: Mean Diastolic Blood Pressure 10 minutes post-sugammadex	46.8 mm Hg Standard Deviation 8.9
Vital Sign: Mean Diastolic Blood Pressure 30 minutes post-sugammadex	43.7 mm Hg Standard Deviation 9.4
Vital Sign: Mean Diastolic Blood Pressure Post-anesthetic	67.8 mm Hg Standard Deviation 13.2
Vital Sign: Mean Diastolic Blood Pressure Screening	58.2 mm Hg Standard Deviation 6.2
Vital Sign: Mean Diastolic Blood Pressure Pre-Rocuronium	51.2 mm Hg Standard Deviation 13.6
Vital Sign: Mean Diastolic Blood Pressure Baseline pre-sugammadex	45.2 mm Hg Standard Deviation 13.3

SECONDARY outcome

Timeframe: Screening up to 1 day after surgery

Population: AST consisting of all participants who received a dose of sugammadex

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

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Vital Sign: Mean Heart Rate 10 minutes post-sugammadex	80.2 Beats per minute Standard Deviation 20.4
Vital Sign: Mean Heart Rate 30 minutes post-sugammadex	77.8 Beats per minute Standard Deviation 20.1
Vital Sign: Mean Heart Rate Post-anesthetic	71.8 Beats per minute Standard Deviation 11.1
Vital Sign: Mean Heart Rate Screening	81.7 Beats per minute Standard Deviation 22.6
Vital Sign: Mean Heart Rate Pre-Rocuronium	78.0 Beats per minute Standard Deviation 21.4
Vital Sign: Mean Heart Rate Baseline pre-sugammadex	83.7 Beats per minute Standard Deviation 21.4
Vital Sign: Mean Heart Rate 2 minutes post-sugammadex	81.0 Beats per minute Standard Deviation 20.8
Vital Sign: Mean Heart Rate 5 minutes post-sugammadex	80.5 Beats per minute Standard Deviation 20.4

SECONDARY outcome

Timeframe: Screening up to day 7

Population: AST consisting of all participants who received a dose of sugammadex

Physical examinations were to be conducted at screening, on Day 1 and 7 days after surgery

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Number of Participants With Physical Examinations Screening	6 participants
Number of Participants With Physical Examinations Peri-procedural (Day 1)	6 participants
Number of Participants With Physical Examinations Day 7	0 participants

SECONDARY outcome

Timeframe: Day 1

Population: AST consisting of all screened participants who received a dose of sugammadex

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Number of Participants With Reoccurrence of Neuromuscular Blockade at Day 1	0 participants

SECONDARY outcome

Timeframe: Day 1

Population: AST consisting of all participants who received a dose of sugammadex

Evidence of AEs due to possible interaction of sugammadex with endogenous compounds or with exogenous compounds other than rocuronium

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Number of Participants With Events Due to Possible Interaction of Sugammadex With Endo-/Exogenous Compounds Other Than Rocuronium	0 participants

SECONDARY outcome

Timeframe: Up to 30 days post -dose

Population: AST consisting of all participants who received a dose of sugammadex

Pregnancies reported by means of a Pregnancy Reporting Form, consist of pregnant female participants or pregnant female partners of male participants

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Number of Participants With Pregnancies at 30 Days Post-dose	0 participants

SECONDARY outcome

Timeframe: Day 1

Population: Intent To Treat (ITT) group consisting of participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Time From Start of Administration of Sugammadex to Recovery of T4/T1 Ratio to 0.9	5.11 Minutes Interval 3.06 to 8.53

SECONDARY outcome

Timeframe: Day 1

Population: ITT group consisting of participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Time From Start of Administration of Sugammadex to Recovery of T4/T1 Ratio to 0.8	4.05 Minutes Interval 2.36 to 6.93

SECONDARY outcome

Timeframe: Day 1

Population: ITT group consisting of participants who received a dose of sugammadex and had at least one efficacy measurement

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.

Outcome measures

Measure	Sugammadex n=6 Participants IV single bolus dose of 4.0 mg/kg sugammadex
Time From Start of Administration of Sugammadex to Recovery of T4/T1 Ratio to 0.7	3.41 Minutes Interval 1.9 to 6.15

Adverse Events

Sugammadex

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	Sugammadex n=6 participants at risk IV single bolus dose of 4.0 mg/kg sugammadex
Cardiac disorders Cardiac failure	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Gastrointestinal disorders Intestinal ischaemia	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Hepatobiliary disorders Hepatic failure	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex

Other adverse events

Measure	Sugammadex n=6 participants at risk IV single bolus dose of 4.0 mg/kg sugammadex
Blood and lymphatic system disorders Thrombocytopenia	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Cardiac disorders Arrhythmia	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Cardiac disorders Cardiac failure	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Gastrointestinal disorders Constipation	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Hepatobiliary disorders Hepatic failure	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Hepatobiliary disorders Hyperbilirubinaemia	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Infections and infestations Post procedural infection	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Infections and infestations Staphylococcal infection	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Infections and infestations Urinary tract infection	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Metabolism and nutrition disorders Hypoglycaemia	33.3% 2/6 • Number of events 2 • Up to 7 days after administration of sugammadex
Musculoskeletal and connective tissue disorders Back pain	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Psychiatric disorders Restlessness	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Renal and urinary disorders Haematuria	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Skin and subcutaneous tissue disorders Decubitis ulcer	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex
Skin and subcutaneous tissue disorders Subcutaneous emphysema	16.7% 1/6 • Number of events 1 • Up to 7 days after administration of sugammadex

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Email: ClinicalTrialsDisclosure@merck.com

Results disclosure agreements

• Principal investigator is a sponsor employee In case a proposed publication contains reference to an invention owned by the sponsor or to which the sponsor otherwise has rights, the sponsor may request a reasonable suspension of the publication.
• Publication restrictions are in place

Restriction type: OTHER