<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03767933</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00073476</org_study_id>
    <nct_id>NCT03767933</nct_id>
  </id_info>
  <brief_title>Non-Steroidal or Opioid Analgesia Use for Children With Musculoskeletal Injuries</brief_title>
  <acronym>No OUCH</acronym>
  <official_title>A Study of Non-Steroidal or Opioid Analgesia Use for Children With Musculoskeletal Injuries: The No OUCH Trials</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alberta</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Manitoba</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centre hospitalier de l'Université de Montréal (CHUM)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Calgary</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Hospital for Sick Children</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Ottawa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Western University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Alberta</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Musculoskeletal (MSK) injuries, including limb injuries, are the most common cause for&#xD;
      Emergency Department (ED) visits for children with pain. Broken arms and legs are known to&#xD;
      cause moderate to severe pain in most children, yet previous research shows that children's&#xD;
      pain in the emergency department is still under-treated. Further, children are less likely to&#xD;
      receive appropriate pain medicine than adults with similar injuries.&#xD;
&#xD;
      The purpose of this research study is to compare the effectiveness and safety of 3 different&#xD;
      possible medication combinations, for the pain management of children with acute MSK limb&#xD;
      injuries. The pain medicines the investigators are studying are ibuprofen (Advil/Motrin),&#xD;
      acetaminophen (Tylenol/Tempra), and hydromorphone (Dilaudid).&#xD;
&#xD;
      This study will consist of 2 trials that will be run simultaneously. Eligible caregiver/&#xD;
      child pairs presenting to the emergency department with acute MSK limb injury will decide in&#xD;
      which trial they wish to participate: the Opioid trial or the Non-Opioid trial. If they&#xD;
      select the Non-opioid trial, they will have an equal chance of receiving either (a) Ibuprofen&#xD;
      OR (b) Ibuprofen and acetaminophen. If they select the Opioid trial, they will have an equal&#xD;
      chance of receiving either (a) Ibuprofen OR (b) Ibuprofen and acetaminophen OR (c) Ibuprofen&#xD;
      and hydromorphone. Regardless of which study they choose, their child will, at minimum,&#xD;
      receive Ibuprofen (Advil/Motrin) for their pain. All study medicines will be given in oral&#xD;
      liquid form.&#xD;
&#xD;
      This study will help the investigators figure out which pain medicine or combination of pain&#xD;
      medicines works best for children with limb injuries. Promotion of adequate acute pain&#xD;
      treatment of children presenting to the ED may help prevent the known short and long-term&#xD;
      effects of inadequately treated pain in children, including unpleasant memories, stress and&#xD;
      anxiety upon future visits to healthcare, and compromised functional outcomes such as missed&#xD;
      school.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale:&#xD;
&#xD;
      Multiple national and international organizations, including the American Academy of&#xD;
      Pediatrics (AAP), have voiced concern over the emergency departments' (EDs) ability and&#xD;
      willingness to provide appropriate analgesia for children's pain. Musculoskeletal (MSK)&#xD;
      injury is a very common cause for ED visits for children with pain, with a child's risk of&#xD;
      sustaining a fracture ranging from 27-42% by the age of 16 years. MSK injury is known to&#xD;
      generate moderate to severe pain in most children and the ED serves as the critical entry&#xD;
      point for these injured children. Despite three decades of pain research in this area, recent&#xD;
      evidence confirms that ED pain management in children is still suboptimal. A retrospective&#xD;
      cohort study of children presenting to the ED with an isolated long-bone fracture showed&#xD;
      almost 1/3 received inadequate medication and 59% received no pain medications during the&#xD;
      critical first hour of assessment. Previous studies have demonstrated that only 35% of&#xD;
      children presenting to a Canadian pediatric ED with fractures or severe sprains received any&#xD;
      analgesic. Further, a medical record review of two Canadian EDs showed unacceptably long&#xD;
      delays in provision of initial analgesia, with children waiting a mean of 118 minutes to the&#xD;
      provision of first analgesia.&#xD;
&#xD;
      The AAP's consensus statement on the assessment and management of pain in children recommends&#xD;
      acetaminophen, ibuprofen, and opioids as the top three medication choices for the treatment&#xD;
      of acute pain in children. These are also the top three most commonly used treatments in the&#xD;
      ED for children with MSK injury pain. It stands to reason that clinicians (and certainly&#xD;
      patients and their families) would prefer medication that has the best efficacy and safety&#xD;
      profile. Although not based on robust evidence, there has recently been a concerted movement&#xD;
      to limit opioid use in children. This is due, in part, to recent controversial publications&#xD;
      and the Centre for Disease Control (CDC)'s position statement regarding opioid use in adults.&#xD;
      Clinicians are increasingly less likely to prescribe oral opioids to younger children, and&#xD;
      caregivers are increasingly less willing to accept or administer them.&#xD;
&#xD;
      Clinicians are currently seeking effective (and for many, non-opioid) oral analgesic options&#xD;
      for their pediatric patients. Researchers have yet to identify the optimal acute pain&#xD;
      management strategy for children with a suspected fracture, as very few studies of analgesic&#xD;
      combination therapy for this injury exist, and monotherapy has been shown to be inadequate&#xD;
      50% of the time. This team's previous work has demonstrated that a combination of oral&#xD;
      morphine with ibuprofen was no more effective and was less safe than oral ibuprofen, alone,&#xD;
      for suspected fracture pain. Similarly, oxycodone was no more effective and was less safe&#xD;
      than ibuprofen for post-discharge fracture pain. There is some emerging work from non-ED&#xD;
      settings to suggest that oral hydromorphone may be an effective alternative to these two&#xD;
      opioid medications. The investigators wish to study if acetaminophen or hydromorphone, when&#xD;
      added to ibuprofen, offers more clinical pain relief than ibuprofen alone. They also wish to&#xD;
      study if the combination of hydromorphone and ibuprofen is more clinically effective than the&#xD;
      combination of acetaminophen with ibuprofen. This study, which will consist of two clinical&#xD;
      trials, will inform health-care decisions by providing evidence for the effectiveness and&#xD;
      safety of commonly prescribed analgesic combination therapies, and compare them to the most&#xD;
      commonly used monotherapy, ibuprofen.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      This study will be comprised of two Phase 2, six-centre, randomized, double blind,&#xD;
      placebo-controlled trials that will be run simultaneously. These two 'sister trials will be&#xD;
      run simultaneously within this novel preference-informed complementary trial design.&#xD;
      Caregiver/child pairs presenting to the ED with acute MSK limb injury will decide in which&#xD;
      trial they wish to participate: the Opioid trial or the Non-Opioid trial.&#xD;
&#xD;
      Those willing to consider an Opioid will be randomized to receive either single-dose: (a)&#xD;
      oral ibuprofen (10mg/kg, max 600mg) plus 2 placebos (both oral hydromorphone and&#xD;
      acetaminophen), OR (b) oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen (15 mg/kg,&#xD;
      max 1000mg) plus hydromorphone placebo OR (c) oral ibuprofen (10mg/kg) + oral hydromorphone&#xD;
      (0.05 mg/kg, max 5 mg) plus acetaminophen placebo. Those not willing to consider an opioid&#xD;
      will be enrolled in the Non-Opioid trial and will be randomized to receive a single dose of&#xD;
      (a) oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen (15 mg/kg, max 1000mg) OR (b)&#xD;
      oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen placebo. Those without a preference&#xD;
      for either trial will be assigned to the Opioid trial, as this one includes all three options&#xD;
      of possible medication combinations. The investigators will measure pain scores, assess&#xD;
      safety, and acquire other study measures, at designated study time points.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 20, 2019</start_date>
  <completion_date type="Actual">March 22, 2023</completion_date>
  <primary_completion_date type="Actual">March 9, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This study will be comprised of two Phase 2, six-centre, randomized, double blind, placebo-controlled trials that will be run simultaneously. The investigators expect that the number of participants recruited and the time to completion of both trials will be more efficient as recruitment for both will occur simultaneously. They propose to conduct this study with a novel preference-informed complementary trial design, in which they will conduct two simultaneous 'sister' trials. Caregiver/child pairs presenting to the ED with acute MSK limb injury will decide in which trial they wish to participate: the Opioid trial or the Non-Opioid trial. The design of each trial will be informed by its sister, or complementary, trial. Once the caregiver/child pair has chosen their preferred trial, conduct within each trial will follow traditional randomized, double-blind placebo-controlled superiority trial methodology. Study endpoints will be identical for both trials within this study.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Research staff, emergency department staff, and participants will be masked with respect to the allocated treatment. The data analyst will also be masked using codes that will not identify treatment groups until analysis is complete.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>vNRS Pain Score</measure>
    <time_frame>At 60 minutes post study drug administration (ie. T-60)</time_frame>
    <description>The self-reported vNRS pain score. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pain Score &lt;3</measure>
    <time_frame>At 60 minutes post study drug administration (ie. T-60)</time_frame>
    <description>The proportion of patients with a vNRS pain score &lt;3 at 60 minutes. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Score Reduction of at least 2 points out of 10</measure>
    <time_frame>At 60 minutes post study drug administration (ie. T-60)</time_frame>
    <description>The proportion of patients with a vNRS pain score reduction of at least 2 points out of 10. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Between Group Pain Scores</measure>
    <time_frame>At 30, 60, 90, and 120 minutes post study drug administration, at Time of Medical Examination (approximately 90 minutes after time of recruitment) and at Time of X-Ray (approximately 60 minutes after time of recruitment)</time_frame>
    <description>Between group differences in vNRS pain scores. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Satisfaction with Pain Relief</measure>
    <time_frame>At the time of discharge from the emergency department (approximately 3 hours after time of recruitment)</time_frame>
    <description>Self-reported caregiver and child satisfaction with pain relief and acceptability of study medications, using a previously employed 5 point Likert scale. This scale ranges from very satisfied to very dissatisfied for caregivers, and ranges from very happy to very sad for children.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of Stay</measure>
    <time_frame>At the time of discharge from the emergency department (approximately 3 hours after time of recruitment)</time_frame>
    <description>Emergency Department length of stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Missed Fractures or Dislocations</measure>
    <time_frame>In the 1 week following administration of study medication</time_frame>
    <description>Frequency of missed fractures or dislocations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Additional Analgesic Requirements</measure>
    <time_frame>In the 60 minutes following administration of study medication</time_frame>
    <description>Proportion of children administered a rescue analgesic</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Effective Analgesia</measure>
    <time_frame>At 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)</time_frame>
    <description>Time to effective analgesia, defined as the first vNRS pain score &lt;3 post-intervention</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VAS Pain Scores</measure>
    <time_frame>At 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)</time_frame>
    <description>Children's self-reported pain intensity on the Visual Analog Scale (VAS). The VAS consists of a straight line with the anchor 'no pain' on one end and 'the worst imaginable pain' at the other end. It is a validated measure for the assessment of pain in children.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FPS-R Pain Scores</measure>
    <time_frame>At 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)</time_frame>
    <description>Children's self-reported pain intensity on the Faces Pain Scale-Revised (FPS-R). The FPS-R consists of 6 faces, from left to right, each showing a greater level of pain than the previous one, with scores varying from 0 (no pain), 2, 4, 6, 8, and 10 (very much pain). The FPS-R is a validated measure for the assessment of pain in children.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>Up to 24 hours post study drug administration</time_frame>
    <description>Proportion of children with adverse events related to study drug administration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serious Adverse Events</measure>
    <time_frame>Up to 24 hours post study drug administration</time_frame>
    <description>Proportion of children with any serious adverse events during the study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RSS</measure>
    <time_frame>At 0, 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)</time_frame>
    <description>Proportion of children in each study group with a Ramsay Sedation Score (RSS) score between 1 to 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Specific Adverse Events</measure>
    <time_frame>Up to 24 hours post study drug administration</time_frame>
    <description>Proportion of children with each specific adverse event type during the study period</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">710</enrollment>
  <condition>Musculoskeletal Injury</condition>
  <arm_group>
    <arm_group_label>Non-Opioid Trial: Arm 1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen placebo, both administered once during the study at the time of recruitment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-Opioid Trial: Arm 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen (15mg/kg, maximum 1000mg), both administered once during the study at the time of recruitment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Opioid Trial: Arm 1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen placebo + Oral hydromorphone placebo, all administered once during the study at the time of recruitment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Opioid Trial: Arm 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen (15mg/kg, maximum 1000mg) + Oral hydromorphone placebo, all administered once during the study at the time of recruitment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Opioid Trial: Arm 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen placebo + Oral hydromorphone (0.05mg/kg, maximum 5 mg), all administered once during the study at the time of recruitment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibuprofen</intervention_name>
    <description>10mg/kg, maximum 600mg; Oral liquid</description>
    <arm_group_label>Non-Opioid Trial: Arm 1</arm_group_label>
    <arm_group_label>Non-Opioid Trial: Arm 2</arm_group_label>
    <arm_group_label>Opioid Trial: Arm 1</arm_group_label>
    <arm_group_label>Opioid Trial: Arm 2</arm_group_label>
    <arm_group_label>Opioid Trial: Arm 3</arm_group_label>
    <other_name>Advil</other_name>
    <other_name>Motrin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen</intervention_name>
    <description>15mg/kg, maximum 1000mg; Oral liquid</description>
    <arm_group_label>Non-Opioid Trial: Arm 2</arm_group_label>
    <arm_group_label>Opioid Trial: Arm 2</arm_group_label>
    <other_name>Tylenol</other_name>
    <other_name>Tempra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydromorphone</intervention_name>
    <description>0.05mg/kg, maximum 5 mg; Oral liquid</description>
    <arm_group_label>Opioid Trial: Arm 3</arm_group_label>
    <other_name>Dilaudid</other_name>
    <other_name>pms-Hydromorphone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen placebo</intervention_name>
    <description>Oral liquid</description>
    <arm_group_label>Non-Opioid Trial: Arm 1</arm_group_label>
    <arm_group_label>Opioid Trial: Arm 1</arm_group_label>
    <arm_group_label>Opioid Trial: Arm 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydromorphone placebo</intervention_name>
    <description>Oral liquid</description>
    <arm_group_label>Opioid Trial: Arm 1</arm_group_label>
    <arm_group_label>Opioid Trial: Arm 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Child aged 6-17 years&#xD;
&#xD;
          2. Presenting to the emergency department with an acute limb injury (&lt;24 hours old) that&#xD;
             is neither obviously deformed nor having neuro-vascular compromise (as assessed by the&#xD;
             triage nurse)&#xD;
&#xD;
          3. Self-reported pain score &gt; 5 on the 0 to 10 verbal Numerical Rating Scale at triage&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Deemed to require immediate intravenous (IV) or intranasal (IN) pain medications by&#xD;
             the clinical team&#xD;
&#xD;
          2. Previously known hypersensitivity to study medications&#xD;
&#xD;
          3. Acetaminophen or NSAID use within 3 hours prior to recruitment&#xD;
&#xD;
          4. Opioid use within 1 hour prior to recruitment&#xD;
&#xD;
          5. Caregiver and/or child cognitive impairment precluding the ability to self-report pain&#xD;
             or respond to study questions&#xD;
&#xD;
          6. Injury suspected to be due to non-accidental trauma/ child abuse (as assessed by the&#xD;
             triage nurse or reported by the family)&#xD;
&#xD;
          7. Suspected multi-limb fracture&#xD;
&#xD;
          8. Chronic pain that necessitates daily analgesic use&#xD;
&#xD;
          9. Hepatic or renal disease/dysfunction&#xD;
&#xD;
         10. Bleeding disorder&#xD;
&#xD;
         11. Known pregnancy&#xD;
&#xD;
         12. Vomiting that precludes the ability to take oral medications (as determined by the&#xD;
             family)&#xD;
&#xD;
         13. Caregiver and/or child inability to communicate fluently in English or French in the&#xD;
             absence of a native language interpreter&#xD;
&#xD;
         14. Caregiver unavailable for follow-up&#xD;
&#xD;
         15. Previous enrolment in the NO OUCH study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Samina Ali, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Alberta/Stollery Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Alberta Children's Hospital</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T3B 6A9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stollery Children's Hospital Emergency Department</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 2B7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Winnipeg</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R3A 1S1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Childrens Hospital at London Health Sciences</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5W9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Eastern Ontario</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Sainte-Justine</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>HT3 1C5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>November 21, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 7, 2018</study_first_posted>
  <last_update_submitted>April 6, 2023</last_update_submitted>
  <last_update_submitted_qc>April 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pediatrics</keyword>
  <keyword>Emergency</keyword>
  <keyword>Analgesia</keyword>
  <keyword>Opioids</keyword>
  <keyword>Combination therapy</keyword>
  <keyword>Ibuprofen</keyword>
  <keyword>Acetaminophen</keyword>
  <keyword>Hydromorphone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
    <mesh_term>Ibuprofen</mesh_term>
    <mesh_term>Hydromorphone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>This study will comply with the CIHR Open Access Policy. The trials will be registered at ClinicalTrials.gov, and results information from this study will be submitted to ClinicalTrials.gov. Also, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 2 years after the completion of the primary endpoint by contacting the Women and Children's Health Research Institute (WCHRI) Data Coordinating Center (DCC). Conduct, reporting, editing, and publication of resultant scholarly work will be guided by the International Committee of Journal Medical Editors (ICJME)'s published recommendations.&#xD;
The identity of participants will not be revealed in any published data or in presentation of the information obtained as a result of this study.</ipd_description>
    <ipd_time_frame>Data from this study may be requested from other researchers 2 years after the completion of the primary endpoint</ipd_time_frame>
    <ipd_access_criteria>Researchers will need to contact the WCHRI DCC for access to the data</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03767933
org study id: Pro00073476
nct id: NCT03767933
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
Musculoskeletal (MSK) injuries, including limb injuries, are the most common cause for
      Emergency Department (ED) visits for children with pain. Broken arms and legs are known to
      cause moderate to severe pain in most children, yet previous research shows that children's
      pain in the emergency department is still under-treated. Further, children are less likely to
      receive appropriate pain medicine than adults with similar injuries.

      The purpose of this research study is to compare the effectiveness and safety of 3 different
      possible medication combinations, for the pain management of children with acute MSK limb
      injuries. The pain medicines the investigators are studying are ibuprofen (Advil/Motrin),
      acetaminophen (Tylenol/Tempra), and hydromorphone (Dilaudid).

      This study will consist of 2 trials that will be run simultaneously. Eligible caregiver/
      child pairs presenting to the emergency department with acute MSK limb injury will decide in
      which trial they wish to participate: the Opioid trial or the Non-Opioid trial. If they
      select the Non-opioid trial, they will have an equal chance of receiving either (a) Ibuprofen
      OR (b) Ibuprofen and acetaminophen. If they select the Opioid trial, they will have an equal
      chance of receiving either (a) Ibuprofen OR (b) Ibuprofen and acetaminophen OR (c) Ibuprofen
      and hydromorphone. Regardless of which study they choose, their child will, at minimum,
      receive Ibuprofen (Advil/Motrin) for their pain. All study medicines will be given in oral
      liquid form.

      This study will help the investigators figure out which pain medicine or combination of pain
      medicines works best for children with limb injuries. Promotion of adequate acute pain
      treatment of children presenting to the ED may help prevent the known short and long-term
      effects of inadequately treated pain in children, including unpleasant memories, stress and
      anxiety upon future visits to healthcare, and compromised functional outcomes such as missed
      school.
Rationale:

      Multiple national and international organizations, including the American Academy of
      Pediatrics (AAP), have voiced concern over the emergency departments' (EDs) ability and
      willingness to provide appropriate analgesia for children's pain. Musculoskeletal (MSK)
      injury is a very common cause for ED visits for children with pain, with a child's risk of
      sustaining a fracture ranging from 27-42% by the age of 16 years. MSK injury is known to
      generate moderate to severe pain in most children and the ED serves as the critical entry
      point for these injured children. Despite three decades of pain research in this area, recent
      evidence confirms that ED pain management in children is still suboptimal. A retrospective
      cohort study of children presenting to the ED with an isolated long-bone fracture showed
      almost 1/3 received inadequate medication and 59% received no pain medications during the
      critical first hour of assessment. Previous studies have demonstrated that only 35% of
      children presenting to a Canadian pediatric ED with fractures or severe sprains received any
      analgesic. Further, a medical record review of two Canadian EDs showed unacceptably long
      delays in provision of initial analgesia, with children waiting a mean of 118 minutes to the
      provision of first analgesia.

      The AAP's consensus statement on the assessment and management of pain in children recommends
      acetaminophen, ibuprofen, and opioids as the top three medication choices for the treatment
      of acute pain in children. These are also the top three most commonly used treatments in the
      ED for children with MSK injury pain. It stands to reason that clinicians (and certainly
      patients and their families) would prefer medication that has the best efficacy and safety
      profile. Although not based on robust evidence, there has recently been a concerted movement
      to limit opioid use in children. This is due, in part, to recent controversial publications
      and the Centre for Disease Control (CDC)'s position statement regarding opioid use in adults.
      Clinicians are increasingly less likely to prescribe oral opioids to younger children, and
      caregivers are increasingly less willing to accept or administer them.

      Clinicians are currently seeking effective (and for many, non-opioid) oral analgesic options
      for their pediatric patients. Researchers have yet to identify the optimal acute pain
      management strategy for children with a suspected fracture, as very few studies of analgesic
      combination therapy for this injury exist, and monotherapy has been shown to be inadequate
      50% of the time. This team's previous work has demonstrated that a combination of oral
      morphine with ibuprofen was no more effective and was less safe than oral ibuprofen, alone,
      for suspected fracture pain. Similarly, oxycodone was no more effective and was less safe
      than ibuprofen for post-discharge fracture pain. There is some emerging work from non-ED
      settings to suggest that oral hydromorphone may be an effective alternative to these two
      opioid medications. The investigators wish to study if acetaminophen or hydromorphone, when
      added to ibuprofen, offers more clinical pain relief than ibuprofen alone. They also wish to
      study if the combination of hydromorphone and ibuprofen is more clinically effective than the
      combination of acetaminophen with ibuprofen. This study, which will consist of two clinical
      trials, will inform health-care decisions by providing evidence for the effectiveness and
      safety of commonly prescribed analgesic combination therapies, and compare them to the most
      commonly used monotherapy, ibuprofen.

      Methods:

      This study will be comprised of two Phase 2, six-centre, randomized, double blind,
      placebo-controlled trials that will be run simultaneously. These two 'sister trials will be
      run simultaneously within this novel preference-informed complementary trial design.
      Caregiver/child pairs presenting to the ED with acute MSK limb injury will decide in which
      trial they wish to participate: the Opioid trial or the Non-Opioid trial.

      Those willing to consider an Opioid will be randomized to receive either single-dose: (a)
      oral ibuprofen (10mg/kg, max 600mg) plus 2 placebos (both oral hydromorphone and
      acetaminophen), OR (b) oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen (15 mg/kg,
      max 1000mg) plus hydromorphone placebo OR (c) oral ibuprofen (10mg/kg) + oral hydromorphone
      (0.05 mg/kg, max 5 mg) plus acetaminophen placebo. Those not willing to consider an opioid
      will be enrolled in the Non-Opioid trial and will be randomized to receive a single dose of
      (a) oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen (15 mg/kg, max 1000mg) OR (b)
      oral ibuprofen (10mg/kg, max 600mg) + oral acetaminophen placebo. Those without a preference
      for either trial will be assigned to the Opioid trial, as this one includes all three options
      of possible medication combinations. The investigators will measure pain scores, assess
      safety, and acquire other study measures, at designated study time points.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This study will be comprised of two Phase 2, six-centre, randomized, double blind, placebo-controlled trials that will be run simultaneously. The investigators expect that the number of participants recruited and the time to completion of both trials will be more efficient as recruitment for both will occur simultaneously. They propose to conduct this study with a novel preference-informed complementary trial design, in which they will conduct two simultaneous 'sister' trials. Caregiver/child pairs presenting to the ED with acute MSK limb injury will decide in which trial they wish to participate: the Opioid trial or the Non-Opioid trial. The design of each trial will be informed by its sister, or complementary, trial. Once the caregiver/child pair has chosen their preferred trial, conduct within each trial will follow traditional randomized, double-blind placebo-controlled superiority trial methodology. Study endpoints will be identical for both trials within this study.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Research staff, emergency department staff, and participants will be masked with respect to the allocated treatment. The data analyst will also be masked using codes that will not identify treatment groups until analysis is complete.
measure: vNRS Pain Score
time frame: At 60 minutes post study drug administration (ie. T-60)
description: The self-reported vNRS pain score. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.
measure: Pain Score <3
time frame: At 60 minutes post study drug administration (ie. T-60)
description: The proportion of patients with a vNRS pain score <3 at 60 minutes. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.
measure: Pain Score Reduction of at least 2 points out of 10
time frame: At 60 minutes post study drug administration (ie. T-60)
description: The proportion of patients with a vNRS pain score reduction of at least 2 points out of 10. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.
measure: Between Group Pain Scores
time frame: At 30, 60, 90, and 120 minutes post study drug administration, at Time of Medical Examination (approximately 90 minutes after time of recruitment) and at Time of X-Ray (approximately 60 minutes after time of recruitment)
description: Between group differences in vNRS pain scores. The 11 point 0-10 verbal Numerical Rating Scale (vNRS) is the most commonly used pain measurement tool for our study age group and has been validated in a number of children's pain studies.
measure: Satisfaction with Pain Relief
time frame: At the time of discharge from the emergency department (approximately 3 hours after time of recruitment)
description: Self-reported caregiver and child satisfaction with pain relief and acceptability of study medications, using a previously employed 5 point Likert scale. This scale ranges from very satisfied to very dissatisfied for caregivers, and ranges from very happy to very sad for children.
measure: Length of Stay
time frame: At the time of discharge from the emergency department (approximately 3 hours after time of recruitment)
description: Emergency Department length of stay
measure: Missed Fractures or Dislocations
time frame: In the 1 week following administration of study medication
description: Frequency of missed fractures or dislocations
measure: Additional Analgesic Requirements
time frame: In the 60 minutes following administration of study medication
description: Proportion of children administered a rescue analgesic
measure: Time to Effective Analgesia
time frame: At 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)
description: Time to effective analgesia, defined as the first vNRS pain score <3 post-intervention
measure: VAS Pain Scores
time frame: At 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)
description: Children's self-reported pain intensity on the Visual Analog Scale (VAS). The VAS consists of a straight line with the anchor 'no pain' on one end and 'the worst imaginable pain' at the other end. It is a validated measure for the assessment of pain in children.
measure: FPS-R Pain Scores
time frame: At 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)
description: Children's self-reported pain intensity on the Faces Pain Scale-Revised (FPS-R). The FPS-R consists of 6 faces, from left to right, each showing a greater level of pain than the previous one, with scores varying from 0 (no pain), 2, 4, 6, 8, and 10 (very much pain). The FPS-R is a validated measure for the assessment of pain in children.
measure: Adverse Events
time frame: Up to 24 hours post study drug administration
description: Proportion of children with adverse events related to study drug administration.
measure: Serious Adverse Events
time frame: Up to 24 hours post study drug administration
description: Proportion of children with any serious adverse events during the study period
measure: RSS
time frame: At 0, 30, 60, 90, and 120 minutes post study drug administration, and at the Time of Medical Examination (approximately 90 minutes after time of recruitment) and Time of X-Ray (approximately 60 minutes after time of recruitment)
description: Proportion of children in each study group with a Ramsay Sedation Score (RSS) score between 1 to 3
measure: Specific Adverse Events
time frame: Up to 24 hours post study drug administration
description: Proportion of children with each specific adverse event type during the study period
arm group label: Non-Opioid Trial: Arm 1
arm group type: Active Comparator
description: Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen placebo, both administered once during the study at the time of recruitment.
arm group label: Non-Opioid Trial: Arm 2
arm group type: Experimental
description: Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen (15mg/kg, maximum 1000mg), both administered once during the study at the time of recruitment.
arm group label: Opioid Trial: Arm 1
arm group type: Active Comparator
description: Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen placebo + Oral hydromorphone placebo, all administered once during the study at the time of recruitment.
arm group label: Opioid Trial: Arm 2
arm group type: Experimental
description: Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen (15mg/kg, maximum 1000mg) + Oral hydromorphone placebo, all administered once during the study at the time of recruitment.
arm group label: Opioid Trial: Arm 3
arm group type: Experimental
description: Oral ibuprofen (10mg/kg, max 600mg) + Oral acetaminophen placebo + Oral hydromorphone (0.05mg/kg, maximum 5 mg), all administered once during the study at the time of recruitment.
intervention type: Drug
intervention name: Ibuprofen
description: 10mg/kg, maximum 600mg; Oral liquid
arm group label: Non-Opioid Trial: Arm 1
arm group label: Non-Opioid Trial: Arm 2
arm group label: Opioid Trial: Arm 1
arm group label: Opioid Trial: Arm 2
arm group label: Opioid Trial: Arm 3
other name: Advil
other name: Motrin
intervention type: Drug
intervention name: Acetaminophen
description: 15mg/kg, maximum 1000mg; Oral liquid
arm group label: Non-Opioid Trial: Arm 2
arm group label: Opioid Trial: Arm 2
other name: Tylenol
other name: Tempra
intervention type: Drug
intervention name: Hydromorphone
description: 0.05mg/kg, maximum 5 mg; Oral liquid
arm group label: Opioid Trial: Arm 3
other name: Dilaudid
other name: pms-Hydromorphone
intervention type: Drug
intervention name: Acetaminophen placebo
description: Oral liquid
arm group label: Non-Opioid Trial: Arm 1
arm group label: Opioid Trial: Arm 1
arm group label: Opioid Trial: Arm 3
intervention type: Drug
intervention name: Hydromorphone placebo
description: Oral liquid
arm group label: Opioid Trial: Arm 1
arm group label: Opioid Trial: Arm 2
criteria: 
gender: All
minimum age: 6 Years
maximum age: 17 Years
healthy volunteers: No
last name: Samina Ali, MD
role: Principal Investigator
affiliation: University of Alberta/Stollery Children's Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Wounds and Injuries
mesh term: Acetaminophen
mesh term: Ibuprofen
mesh term: Hydromorphone
sharing ipd: Yes
ipd description: This study will comply with the CIHR Open Access Policy. The trials will be registered at ClinicalTrials.gov, and results information from this study will be submitted to ClinicalTrials.gov. Also, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 2 years after the completion of the primary endpoint by contacting the Women and Children's Health Research Institute (WCHRI) Data Coordinating Center (DCC). Conduct, reporting, editing, and publication of resultant scholarly work will be guided by the International Committee of Journal Medical Editors (ICJME)'s published recommendations.
The identity of participants will not be revealed in any published data or in presentation of the information obtained as a result of this study.
ipd time frame: Data from this study may be requested from other researchers 2 years after the completion of the primary endpoint
ipd access criteria: Researchers will need to contact the WCHRI DCC for access to the data