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Sugammadex

Phase 3

Neuromuscular Blockade | Small molecule | Other |Merck & Company, Inc.|Last Updated: Feb 12, 2021

Success Probability
Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
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Market & Valuation
rNPV $3.2B
Market Size $9.4B
Revenue Basis $1.6B
Competitors 6
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Trial Design
RandomizedDouble-BlindPLACEBO_CONTROLLEDDMCBiomarker
Total Trials5
Total Enrollment1,522
FDA Designations
No designations recorded
Clinical Trials (5)
NCT IDTitlePhaseStatusEnrollmentVelocityDesignStartCompletionLast UpdatedSitesCountries
NCT01422304Reversal of Neuromuscular Blockade With Sugammadex or Usual Care in Hip Fracture Surgery or Joint (Hip/Knee) Replacement (P07038)PHASE3 COMPLETED 1,198Oct 12, 2011Sep 26, 2012Feb 12, 2021 -
NCT01050543Comparison of Sugammadex With Neostigmine as Reversal Agents for Rocuronium at Reappearance of T2 (Study P06101)PHASE3 COMPLETED 128Feb 1, 2010Aug 20, 2010Jul 2, 2017 -
NCT00656799Dialysis of Sugammadex in Participants With Severe Renal Impairment (Study 19.4.333) (P05773)PHASE3 COMPLETED 6Apr 1, 2008Jul 1, 2009Mar 10, 2015 -
NCT00535496Relation Between TOF-Watch® SX and a Peripheral Nerve Stimulator After 4.0 mg.Kg-1 Sugammadex (P05698)PHASE3 COMPLETED 91Sep 1, 2007Feb 1, 2008Mar 17, 2015 -
NCT03519854Efficacy, Safety and Pharmacokinetics of Sugammadex (Org 25969; MK-8616) at 3 Different Time Points After 0.6 mg/kg Esmeron® in Male Participants (P05940; MK-8616-020).PHASE2 COMPLETED 99Dec 1, 2002Jun 1, 2003Apr 2, 2019 -
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Study Endpoints
Primary Endpoints
Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 24 Hours After Study Drug Administration
Up to 24 hours post study drug administration

Post-treatment events of bleeding were evaluated by a medically-qualified, blinded member of the surgical team (Blinded Safety Assessor), in consultation with the surgeon, to determine if an event was a "suspected, unanticipated adverse event of bleeding" (SUAEB). A SUAEB is an event of bleeding outside the usual boundaries of expectations for a participant (e.g., in amount of blood lost, prolonged duration of bleeding, or other factors) considering the type of procedure as well as participant's specific surgical experience and underlying risk of bleeding. In addition, blinded review of clinical and laboratory databases was performed to identify any event potentially consistent with a SUAEB; these were reviewed by the Blinded Safety Assessor, who determined if any was a SUAEB. All SUAEBs were evaluated by a blinded external Adjudication Committee, which classified each as either: 1) a major bleeding event, 2) a non-major bleeding event, or 3) not an unanticipated event of bleeding.

Time From Start of Study Drug Administration to Recovery of the T4/T1 Ratio to 0.9
From Start of Study Drug Administration to Recovery of the T4/T1 Ratio to 0.9 (estimated from 2 minutes up to ~15 minutes)

Neuromuscular functioning was monitored by applying repetitive Train-Of-Four (TOF) electrical stimulations to the ulnar nerve every 15 seconds \& assessing twitch response at the adductor pollicis muscle. T1 \& T4 refer to the magnitudes (height) of the 1st \& 4th 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. In this study, twitch responses were recorded until the T4/T1 Ratio reached \>= 0.9, the minimum acceptable ratio that indicated complete recovery.

Clearance of Sugammadex by Dialysis as Measured by the Reduction Ratio (RR)
Up to day 7

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.

Clearance of Rocuronium by Dialysis as Measured by the Reduction Ratio (RR)
Up to Day 7

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.

Rate of Clearance of Sugammadex From Blood
Up to day 7

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.

Rate of Clearance of Rocuronium From Blood
Up to Day 7

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.

Rate of Clearance of Sugammadex From Dialysate
Up to day 7

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.

Rate of Clearance of Rocuronium From Dialysate
Up to Day 7

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.

Time From Start of Administration of 4.0 mg/kg Sugammadex to Recovery of the T4/T1 Ratio to 0.9 Measured by a TOF-Watch® SX
Up to 4 minutes after administering sugammadex

Neuromuscular function was monitored by applying repetitive TOF electrical stimulations with the TOF-Watch® SX to the ulnar nerve of one forearm every 15 seconds \& assessing twitch response at the adductor pollicis muscle with the TOF-Watch® SX. T1 and T4 are the magnitudes (heights) of the first and fourth twitches respectively after TOF nerve stimulation, where stimulation was continued until the T4/T1 ratio reached 0.9. A higher T4/T1 ratio indicates a lower degree of neuromuscular blockade, with a value of 1.0 representing full recovery. Only participants treated with 4.0 mg/kg sugammadex are presented, where the TOF-Watch® SX on the dominant forearm n =30, and on the non-dominant forearm n = 31. The 1.0 mg/kg sugammadex group was not evaluated for this outcome measure.

Time From Start of Administration of 4.0 mg/kg Sugammadex to Reappearance of T4 Measured by a Peripheral Nerve Stimulator (PNS)
up to 2 minutes after administering sugammadex

Neuromuscular function was monitored with a PNS by applying repetitive TOF stimulation to the ulnar nerve of one forearm every 15 seconds and assessing the number of twitches at the adductor pollicis muscle by a blinded PNS assessor. T4 is the fourth twitch after TOF nerve stimulation. Only participants treated with 4.0 mg/kg sugammadex are presented, where the PNS on the dominant forearm n =31, and on the non-dominant forearm n = 30. The 1.0 mg/kg sugammadex group was not evaluated for this outcome measure.

Difference in Time Between Recovery of T4/T1 Ratio to 0.9 as Measured by TOF Watch® SX, and Reappearance of T4 as Measured by PNS, Within Participants, After Administration of 4.0 mg/kg Sugammadex
Up to 3 minutes after administering sugammadex

The difference between the recovery of T4/T1 ratio to 0.9 and reappearance of T4 within participants was assessed from an ANOVA method. Only participants treated with 4.0 mg/kg sugammadex are presented, where the TOF-Watch® SX on the dominant forearm n =30, and on the non-dominant forearm n = 31; and the PNS on the dominant forearm n =31, and on the non-dominant forearm n = 30. The 1.0 mg/kg sugammadex group was not evaluated for this outcome measure.

Mean Time From Start of Study Treatment Administration to Recovery of the T4/T1 Ratio to 0.9
Up to 70 minutes following administration of study treatment

Mean time from start of study treatment administration to recovery of participant T4/T1 ratio to 0.9 was assessed through the repeated application (every 15 seconds) of an electrical stimulation protocol. Specifically, 4 electrical stimulations were applied to the ulnar nerve and the magnitude of the twitch response of the adductor pollicis muscle (i.e. thumb twitch response) was assessed. With T4 and T1 referring to the respective magnitude of the fourth and first thumb twitch during nerve stimulation, the T4/T1 ratio indicates the current degree of neuromuscular blockade (NMB) present in the participant as a decimal from 0 (loss of T4 twitch) to 1 (no NMB). Further, reduced recovery time of the T4/T1 ratio to 0.9 indicates faster recovery from NMB. Summary data, originally presented in the format of units "minutes:seconds" (mm:ss), was reformatted to be presented in the single unit of "minutes" (min).

Secondary Endpoints
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) at 10 and 60 Minutes Post Study Drug Administration
Baseline, 10 and 60 minutes post study drug administration
Percent Change From Baseline in Prothrombin Time (International Normalized Ratio) (PT[INR]) at 10 and 60 Minutes Post Study Drug Administration
Baseline, 10 and 60 minutes post study drug administration
Number of Participants With One or More Adjudicated Events of Bleeding (Major or Non-major) With Onset Within 14 Days After Study Drug Administration
Up to 14 days post study drug administration
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Study Design & Arms
AllocationRANDOMIZED
MaskingTRIPLE
ModelPARALLEL
PurposeTREATMENT
Treatment Arms
ArmTypeDescription
SugammadexEXPERIMENTALPrior to randomization, participants will be assigned to planned active reversal or planned spontaneous recovery by the anesthesiologist according to the recovery method the anesthesiologist would have chosen if the participant were not in the study. In this treatment arm, participants assigned to planned active reversal will receive sugammadex and placebo to neostigmine, and participants assigned to planned spontaneous recovery will receive sugammadex. Study drug will be administered after the last dose of rocuronium or vecuronium and after wound closure.
Usual CareEXPERIMENTALPrior to randomization, participants will be assigned to planned active reversal or planned spontaneous recovery by the anesthesiologist according to the recovery method the anesthesiologist would have chosen if the participant were not in the study. In this treatment arm, participants assigned to planned active reversal will receive neostigmine and placebo to sugammadex, and participants assigned to planned spontaneous recovery will receive placebo to sugammadex. Study drug will be administered after the last dose of rocuronium or vecuronium and after wound closure.
NeostigmineACTIVE_COMPARATOR -
1EXPERIMENTALsugammadex 1.0 mg/kg, TOF-Watch® SX (dominant forearm) and PNS (non-dominant forearm)
2EXPERIMENTALsugammadex 1.0 mg/kg, TOF-Watch® SX (non-dominant forearm) and PNS (dominant forearm)
3EXPERIMENTALsugammadex 4.0 mg/kg, TOF-Watch® SX (dominant forearm) and PNS (non-dominant forearm)
4EXPERIMENTALsugammadex 4.0 mg/kg, TOF-Watch® SX (non-dominant forearm) and PNS (dominant forearm)
Arm A. Placebo; given 3 minutes after Esmeron®PLACEBO_COMPARATORPlacebo (single intravenous (IV) bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm B. 1 mg/kg Sugammadex; given 3 minutes after Esmeron®EXPERIMENTALSugammadex (1 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm C. 2 mg/kg Sugammadex; given 3 minutes after Esmeron®EXPERIMENTALSugammadex (2 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm D. 4 mg/kg Sugammadex; given 3 minutes after Esmeron®EXPERIMENTALSugammadex (4 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm E. 6 mg/kg Sugammadex; given 3 minutes after Esmeron®EXPERIMENTALSugammadex (6 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm F. 8 mg/kg Sugammadex; given 3 minutes after Esmeron®EXPERIMENTALSugammadex (8 mg/kg; single IV bolus) administered 3 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm G. Placebo; given 5 minutes after Esmeron®PLACEBO_COMPARATORPlacebo (single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm H. 1 mg/kg Sugammadex; given 5 minutes after Esmeron®EXPERIMENTALSugammadex (1 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm I. 2 mg/kg Sugammadex; given 5 minutes after Esmeron®EXPERIMENTALSugammadex (2 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm J. 4 mg/kg Sugammadex; given 5 minutes after Esmeron®EXPERIMENTALSugammadex (4 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm K. 6 mg/kg Sugammadex; given 5 minutes after Esmeron®EXPERIMENTALSugammadex (6 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm L. 8 mg/kg Sugammadex; given 5 minutes after Esmeron®EXPERIMENTALSugammadex (8 mg/kg; single IV bolus) administered 5 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm M. Placebo; given 15 minutes after Esmeron®PLACEBO_COMPARATORPlacebo (single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm N. 1 mg/kg Sugammadex; given 15 minutes after Esmeron®EXPERIMENTALSugammadex (1 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm O. 2 mg/kg Sugammadex; given 15 minutes after Esmeron®EXPERIMENTALSugammadex (2 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm P. 4 mg/kg Sugammadex; given 15 minutes after Esmeron®EXPERIMENTALSugammadex (4 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm Q. 6 mg/kg Sugammadex; given 15 minutes after Esmeron®EXPERIMENTALSugammadex (6 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Arm R. 8 mg/kg Sugammadex; given 15 minutes after Esmeron®EXPERIMENTALSugammadex (8 mg/kg; single IV bolus) administered 15 minutes after the bolus intubation dose of 0.6 mg/kg Esmeron®.
Interventions
NameTypeDescription
SugammadexDRUGSugammadex 4 mg/kg intravenously
neostigmine and glycopyrrolate or atropineDRUGNeostigmine and glycopyrrolate or neostigmine and atropine administered intravenously per usual practice and per the product labels
Placebo to neostigmineDRUGNormal saline (NaCl 0.9%)
Placebo to sugammadexDRUGNormal saline (NaCl 0.9%)
neostigmineDRUGneostigmine 50 mcg/kg (total dose not to exceed 5.0 mg) combined with glycopyrrolate 10 mcg/kg, single intravenous bolus dose administered within 10 seconds into a fast flowing venous infusion
RocuroniumDRUGAfter achieving stable anesthesia an IV single bolus dose of 0.6 mg/kg rocuronium was administered
PlaceboDRUG0.9% NaCl administered as a fast IV bolus dose (within 30 seconds).
Esmeron®DRUGEsmeron® administered at 0.6 mg/kg as a fast IV bolus (within 10 seconds), dosed according to participant actual body weight.
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Eligibility Criteria
Age Range18 Years — N/A
SexALL
Healthy VolunteersNo

Inclusion Criteria: * Must be American Society of Anesthesiologists (ASA) Class 1, 2, or 3 * Must be scheduled for a hip fracture surgery or joint (hip or knee) replacement surgery under general anesthesia including the use of rocuronium or vecuronium for neuromuscular blockade * Must be: * Curr...

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