Study of Indomethacin Capsules to Treat Pain Following Surgery in Children Ages 6 to <17 Years of Age

This was a phase IIA, multicenter, open-label, fixed-dose study. The study consisted of 3
periods: a Screening Period (Day −14 to Day −1, Preoperative Visit), a Treatment Period (Days
1-3), and a Follow-Up Period (Days 4-14).

Informed consent from the subject's legally authorized representative (parent/guardian) and
assent (as applicable) from the subject were obtained before the subject underwent any
protocol-specified procedures or assessments. Screening/Baseline data (including medical
history, vital signs, physical examination, and clinical laboratory tests) were collected for
each subject and used for initial assessment of eligibility. Clinical laboratory test results
obtained before screening were acceptable for determining eligibility if they were collected
within 1 week before the Screening/Baseline Visit. Subjects must have met all study entry
criteria to be eligible for enrollment. To adequately assess the safety and tolerability of
administering multiple doses of Tivorbex Capsules in this population, subjects who were
likely to require multiple-day treatment for pain (preferably for the full 3-day treatment
period) were enrolled.

As part of screening, subjects were required to demonstrate the ability to swallow a placebo
capsule that corresponded in size to the study drug dose for their body weight. Eligible
subjects were required to refrain from taking prohibited medications throughout the study.
Prohibited analgesic medications taken at the time of the Screening/Baseline Visit were
discontinued 12 hours before the first dose of study drug (perioperative analgesic/anesthetic
medications given during the surgical procedure were exempt from this restriction) and were
captured in the appropriate electronic case report form (eCRF).

Rescue medication as part of the postoperative treatment regimen was permitted according to
the local standard of care unless contraindicated for use with Tivorbex. Subjects could
receive the first dose of Tivorbex any time after surgery, following discontinuation of
intravenous (IV) analgesics, oral opioids, or acetaminophen.

Subjects received the first dose of study drug at the site on Day 1. Four blood samples for
PK analysis were collected at various time points via indwelling catheter over the first 12
hours after initial dosing.

After the last blood sample collection (ie, up to approximately 12 hours after dosing), if
treatment for mild to moderate pain was still needed, the second dose of study drug was
administered. Subjects were instructed to continue dosing as needed up to twice daily for up
to 3 days (through Day 3) or until treatment for pain was no longer needed, whichever came
first.

Subjects remained at the study site until the last blood sample for drug concentration
measurement was obtained in the 8- to 12-hour time interval after the first dose of study
drug and were discharged at the discretion of the investigator. Depending on the nature of
the pediatric surgical procedure, subjects could be managed as inpatients (possibly for the
entire duration of the study) or as outpatients according to the standard of care required to
treat the subject's condition. Upon discharge from the site, the parent/guardian was given a
diary and instructed to record dates/times of study drug administration and concomitant
medications (including rescue medication use). Inpatients did not require a diary because
this information was captured in hospital or site records. Before discharge from the site, a
supply of study drug was dispensed to the subject's parent/guardian.

On Day 1 of the Treatment Period (Day 1 to Day 3), the investigator reviewed
Screening/Baseline Visit assessments (including adverse events [AEs] and concomitant
medications, vital signs, physical examination, and entry criteria) and clinical laboratory
test results. Following surgery, subjects who continued to meet study entry criteria had
their pain severity assessed. Pain severity for children ages 6 to <12 years was assessed
using the FPS R. Pain severity for children ages ≥12 years was assessed using a 0 to 10 NRS.
All subjects were to have a baseline FPS-R score or baseline NRS of >0 and <7 to be eligible
for the study.

Subjects contributed 4 blood samples for PK analysis from 1 of the 2 sampling schemes as
follows:

Sampling Scheme #1 Sampling Scheme #2 0.15 to 0.75 hours 0.75 to 1.25 hours 1.25 to 2.25
hours 1.75 to 3.0 hours 3.0 to 6.0 hours 6.0 to 8.0 hours 8.0 to 10.0 hours 10.0 to 12.0
hours

If a subject experienced inadequate pain relief or increasing pain or severe pain following
Tivorbex treatment, the investigator could consider administration of additional
postoperative analgesic treatment (ie, "rescue medication") according to applicable standards
of care. During study participation, the subject was to refrain from taking any other NSAIDs,
aspirin, or opioid combination products containing NSAIDs or aspirin. If the pain experienced
by a subject continued to be unacceptable following rescue medication administration, the
investigator was to consider withdrawing the subject from the study.

Subjects returned to the site for a Final Visit approximately 7 days (± 3 days) after the
final dose of Tivorbex. During this visit, a physical examination was performed, vital signs
were assessed, and subject diaries were collected and reviewed. The study drug was accounted
for and unused study drug was collected. All AE data were reviewed and recorded. Any ongoing
AE was followed to a satisfactory resolution, until the subject became stable, or until the
event could be explained by another known cause(s) (ie, concurrent condition or medication)
and clinical judgment indicated that further evaluation was not warranted.

Inclusion Criteria:

- Body weight ≥20 kilograms

- Mild to moderate acute pain requiring treatment with analgesic medication

- Willing to have blood samples taken for PK sampling using an indwelling catheter

- Must be able to swallow capsules and can tolerate oral medication

- For females: is not of reproductive potential (defined as premenarchal) or is
practicing an acceptable method of birth control

Exclusion Criteria:

- Severe acute pain

- Chronic analgesic or glucocorticoid use for any condition within 6 months before
dosing with study drug

- Emergency surgery

- History of allergic reaction, hypersensitivity, or clinically significant intolerance
to indomethacin, aspirin, codeine, acetaminophen, or any NSAID

- History of peptic ulcer disease or a GI event (eg, perforation, obstruction, or bleed)
within 6 months before screening

- Current use of any medication that may cause a clinically significant drug interaction
when co-administered with indomethacin

- Current use of any medication that might affect the pharmacokinetics of indomethacin

- History of bleeding disorders

- Developmental delay or behavioral problems that would make it difficult to assess pain

- Impaired liver function

- Clinically significant renal or cardiovascular disease

- Any medical condition that compromises ability to swallow, absorb, metabolize, or
excrete the study drug

- Previously received any investigational product or device within 30 days before
Screening or scheduled to receive an investigational device or another investigational
drug (other than that in this study) during the course of this study

- Previous participation in this clinical study or currently taking indomethacin