Study of Indomethacin Capsules to Treat Pain Following Surgery in Children Ages 6 to <17 Years of Age
Condition: Pain, Postoperative
MeSH terms: Pain, Postoperative
Study type: Interventional
Phase: Phase 2

Summary: 
      The purposes of this study are to evaluate the safety and tolerability and to model the
      single-dose pharmacokinetic profile of indomethacin capsules low dose and high dose in
      children ages 6 to <17 years experiencing mild to moderate acute postoperative pain.
    

Detailed description: 
      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.
    

Intervention name(s): Indomethacin Capsules low dose; Indomethacin Capsules high dose
Intervention type(s): Drug; Drug
Intervention MeSH terms: Indomethacin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment