Phase 4 Double-blinded, Randomized, Active Comparator-controlled
Clinical Trial to Study the Efficacy, Safety, and Pharmacokinetics of Sugammadex (MK-
8616) for Reversal of Neuromuscular Blockade in Pediatric Participants Aged Birth to <2
Years

Neuromuscular blockade is an important component of many surgical and medical
procedures, as it provides muscle relaxation and reduces patient movement. In
current anesthesia practice, reversal agents of NMB are often administered at
the end of the procedure to aid the recovery of muscle function and prevent
residual NMB after the procedure. Prior to the availability of sugammadex, all
clinically used reversal agents (eg,
neostigmine, edrophonium) were acetylcholinesterase inhibitors. These agents
achieved reversal of NMB, but at the cost of multiple side effects due to their
nonselective potentiation of cholinergic neurotransmission. Moreover, these
agents are only able to reverse moderate NMB, a degree of block that requires
partial spontaneous recovery of neuromuscular transmission, which limits their
utility. Reversal of deep NMB is a unique benefit of sugammadex compared to
other current treatments, which can only reverse moderate block. From a risk
perspective, sugammadex has been shown to be generally safe and well tolerated.
The use of sugammadex at recommended doses is associated with a low risk of
residual NMB or recurrence of NMB compared with current treatment. At this
timepoint clinical trial data in children is limited. The Sponsor considers
that the currently approved adult doses are appropriate for assessment to
provide the optimal benefit/risk ratio in this trial, based on the adult Phase
3 trials, subsequent post marketing data, and the pediatric information
collected to date in prior sugammadex trials.

The current trial aims to demonstrate that sugammadex is generally safe and
effective for reversing both moderate and deep block after rocuronium or
vecuronium induced NMB in term neonates and young children.

This is a randomized, active comparator-controlled, parallel-group, multi-site,
double-blinded
trial to evaluate the PK, safety, and efficacy of sugammadex in pediatric
participants aged
birth to <2 years for the reversal of moderate and deep NMB.

The design of this trial consists of a 2-part structure (Part A and Part B).
Part A will be openlabel, while Part B will be double-blinded. Part A will
evaluate safety and confirm the doses of sugammadex that will produce similar
exposure in children from birth to <2 years of age when compared to systemic
exposure noted in adults following administration of the 2 mg/kg and 4 mg/kg
doses. In Part B of this trial, the safety and efficacy parameters of
sugammadex 2 mg/kg and 4 mg/kg will be assessed. Potential trial participants
will have a planned nonemergent
surgical procedure or clinical situation that can be conducted under both
moderate and/or deep NMB.

Enrollment into the trial will begin with Part A, which is further divided into
Panel 1 and Panel 2. First, Panel 1 will evaluate the PK and safety of
sugammadex 2 mg/kg in the setting of moderate block; next, Panel 2 will
evaluate the PK and safety of sugammadex 4 mg/kg in
the deep block setting. Panels 1 and 2 will run in succession and consecutively
within each age cohort.

Participants will be enrolled within 1 of the following 4 age cohorts in a
sequential approach (within each Part), beginning with the eldest age cohort.
Enrollment within each age cohort will be based on the participant*s age at
time of treatment allocation (age will be defined as the anniversary date of
the participant*s actual birthdate):
* 6 months to <2 years
* 3 months to <6 months
* 28 days to <3 months
* Birth to 27 days

There are 5 intervention groups:
Treatment allocation/randomization will occur centrally using interactive
response technology (IRT). Participants will be allocated to 1 treatment group.
Participants in Part A will be assigned the following treatment regimen:
* Panel 1: Moderate block and reversal with sugammadex 2 mg/kg
* Panel 2: Deep block and reversal with sugammadex 4 mg/kg

Participants in Part B of the study will be assigned randomly in a 1:1:1 ratio
to 1 of the following treatment groups:
* Moderate block and reversal with sugammadex 2 mg/kg; or
* Moderate block and reversal with neostigmine 50 mcg/kg; or
* Deep block and reversal with sugammadex 4 mg/kg

For this study, patients will be exposed to invasive procedures such as blood
collection, infusion line, physical examination, ECG monitoring, study
medication administration, parents or guardians will be asked to answer
questions about medication and the health status of their child and will be
requested to visit the hospital for check-up visits and / or a final telephone
contact.

It cannot be guaranteed that participants in clinical studies will directly
benefit from treatment during participation, as clinical studies are designed
to provide information about the safety and effectiveness of an investigational
medicine. However, data from clinical studies in children are limited. Current
research aims to demonstrate that sugammadex is generally safe and effective
for eliminating both moderate and deep blockages following rocuronium or
vecuronium-induced NMB in full-term newborns and young children undergoing
surgery or clinical procedure.

The Sponsor considers that the currently approved adult doses are appropriate
for assessment to provide the optimal benefit/risk ratio in this trial, based
on the adult Phase 3 trials, subsequent post marketing data, and the pediatric
information collected to date in prior sugammadex trials.

Sugammadex has a positive benefit-risk profile and is well tolerated in the
approved indications as described in the IB. It has specifically been shown to
be superior (faster recovery as well as effective in a higher proportion of
treated participants) to both placebo and neostigmine for reversal of moderate
and deep NMB. Reversal of deep NMB is a unique benefit of sugammadex compared
to other current treatments, which can only reverse
moderate block. From a risk perspective, sugammadex has been shown to be
generally safe and well tolerated. The use of sugammadex at recommended doses
is associated with a low risk of residual NMB or recurrence of NMB compared
with current treatment.