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An Efficacy and Safety Study of Tapentadol in the Treatment of Post-operative Acute Pain Requiring Opioid Treatment in Pediatric Participants

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ClinicalTrials.gov Identifier: NCT02081391
Recruitment Status : Recruiting
First Posted : March 7, 2014
Last Update Posted : December 12, 2018
Sponsor:
Collaborator:
Depomed
Information provided by (Responsible Party):
Grünenthal GmbH

Brief Summary:
The purpose of the study is to evaluate the efficacy of tapentadol oral solution, based on the total amount of supplemental opioid analgesic used over 12 hours or 24 hours after initiation of investigational medicinal product in children and adolescents who have undergone surgery that would produce moderate to severe pain during opioid treatment.

Condition or disease Intervention/treatment Phase
Acute Pain Drug: Tapentadol 4 mg/mL Drug: Tapentadol 20 mg/mL Other: Placebo Phase 3

Detailed Description:

The supplemental opioid medication reflecting the standard of care will be available as patient or nurse controlled intravenous morphine or hydromorphone. This supplemental opioid medication will be given to control pain, as needed, in both the treatment and placebo groups.

Children and adolescents 6 months and older will be dosed with a dose regimen of 1.25 mg/kg for the first 24 hours of treatment. 24 hours after the start of study medication (and based on clinical judgment) a dose reduction to 1.0 mg/kg is allowed.

Participants 30 days to less than 6 months old will be dosed with a regimen of 0.5 mg/kg for the first 24 hours of treatment. The dose of study drug (IMP) may be reduced after 24 hours (if there is a reduced need for analgesia according to the investigator's judgment) to 0.3 mg/kg.

Participants aged from birth to less than 30 days old will be dosed with a regimen of 0.1 mg/kg for the first 24 hours of treatment. The dose of study drug (IMP) may be reduced after 24 hours (if there is a reduced need for analgesia according to the investigator's judgment) to 0.075 mg/kg.

A decision to maintain or alter the dose will depend on the effectiveness of the analgesia (pain killer) and the adverse event profile observed in each participant over the first 24 hour dosing period.

In exceptional cases, if a participant has unbearable pain despite using nurse/patient controlled analgesia (NCA/PCA), an additional bolus (defined as a clinician bolus) of morphine or hydromorphone may be administered. The clinician bolus can be given either using the NCA/PCA pump system or by an intravenous bolus injection. The opioid given as a clinician bolus or if the NCA/PCA intravenous line fails must be the same as that used in the NCA/PCA pump system.

Dosing with Investigational Medicinal Product will be stopped if:

  • A switch to exclusively oral opioid analgesic medication is indicated according to the local standard of care.
  • Opioid analgesic medication is no longer needed.
  • Investigational Medicinal Product has been administered for 72 hours. Safety evaluations will include assessment of adverse events, vital signs, laboratory parameters, electrocardiogram, and specific scale to assess suicidal ideation. The maximum study duration for each participant will be 42 days.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: All participants in the European (EU) Pediatric Committee (PDCO) set (which includes completed subjects aged 2 years or older in the US FDA set) will remain locked after the analysis for the first report. Participants under 2 years old in the US FDA set will remain blinded, as independent randomization lists are used for subjects aged less than 2 years old.
Primary Purpose: Treatment
Official Title: An Evaluation of the Efficacy and Safety of Tapentadol Oral Solution in the Treatment of Post-operative Acute Pain Requiring Opioid Treatment in Pediatric Subjects Aged From Birth to Less Than 18 Years Old
Actual Study Start Date : February 19, 2015
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tapentadol IR
Tapentadol immediate release (IR) oral solution 1.25 mg/kg will be given every 4 hours to participants aged 6 months to less than 18 years. Participants 30 days to less than 6 months old will be dosed with 0.5 mg/kg every 4 hours (in the first 24 hours). Participants from birth to less than 30 days of age will be dosed with 0.1 mg/kg every 4 hours (in the first 24 hours).
Drug: Tapentadol 4 mg/mL
Participants will receive tapentadol solution orally (by mouth) every 4 hours for up to 72 hours.

Drug: Tapentadol 20 mg/mL
Participants aged from 6 months to less than 18 years with body weight greater than or equal to 20 kg will receive tapentadol 20 mg/mL solution orally every 4 hours for up to 72 hours. The dose during the first 24 hours will be 1.25 mg/kg. After 24 hours, the dose can be reduced to 1.0 mg/kg, based on investigator's judgment. Dose of tapentadol 20 mg/mL solution for participants aged birth to less than 2 years with body weight greater than or equal to 20 kg will be decided based on the forthcoming pharmacokinetic (PK) data.

Placebo Other: Placebo
Matching placebo solution will be administered orally every 4 hours up to 72 hours.




Primary Outcome Measures :
  1. For US: The total amount of supplemental opioid analgesic medication used within the first 12 hours after first intake of investigational medicinal product (IMP) [tapentadol oral solution or placebo] in participants aged from birth to less than 17 years [ Time Frame: Up to 12 hours ]
  2. For Europe: The total amount of supplemental opioid analgesic (pain killer) medication used within the first 24 hours after first intake of IMP in participants aged from 2 years to less than 18 years [ Time Frame: Up to 24 hours ]

Secondary Outcome Measures :
  1. The total amount of supplemental opioid analgesic medication used within the first 12 hours after the first intake of IMP in participants from 2 years to less than 18 years [ Time Frame: Up to 12 hours ]
  2. The total amount of supplemental opioid analgesic medication used within the first 24 hours after the first intake of IMP in participants aged from birth to less than 17 years [ Time Frame: Up to 24 hours ]
  3. The total amount of supplemental opioid analgesic medication received, assessed in 12 hour intervals from 24 hours to 96 hours after the first dose of IMP [ Time Frame: Up to 96 hours ]
  4. Palatability of IMP in participants aged 2 years to less than 18 years assessed using facial 5-point hedonic scale [ Time Frame: Up to 96 hours ]
    Palatability of IMP will be assessed using 5-point hedonic scales in combination with verbal rating. A question "How does the medication taste" will be asked and the verbal rating will be from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions will be co-related with verbal rating range where 5 = really good, 4 = good, 3 = a bit good/a bit bad, 2 = bad, and 1 = really bad. Higher scores represent good palatability.

  5. Acceptability of IMP in participants aged 2 years to less than 18 years assessed using facial 5-point hedonic scale [ Time Frame: Up to 96 hours ]
    Acceptability of IMP will be assessed using 5-point hedonic scales in combination with verbal rating. A question "Swallowing the medication is" will be asked and the verbal rating will be from really good, good, a bit good/a bit bad, bad, and really bad. The pictorial scale of facial expressions will be co-related with verbal rating range, where 5 = really easy, 4 = easy, 3 = a bit easy/a bit difficult, 2 = difficult, and 1 = really difficult. Higher scores represent good acceptability.

  6. Change from baseline in the Face, Leg, Activity, Cry, and Consolability (FLACC) total score in participants aged less than 6 years [ Time Frame: Up to 96 hours ]
    The FLACC scale is used to measure the pain intensity based on 5 criteria relating to face, legs, activity, crying, and consolability. Each criteria is assigned a score of 0, 1 or 2. The total score is the sum of the 5 individual criteria. Higher scores represent worse condition.

  7. Change from baseline in the Faces Pain Scale-Revised (FPS-R) pain intensity score in participants aged 6 to less than 12 years [ Time Frame: Up to 96 hours ]
    The FPS-R is a validated self-reported 6-point scale with 0 representing no pain and 10 representing very much pain. Facial representations are used to indicate how much the pain hurts. Higher scores represent worse condition.

  8. Change from baseline in the Visual Analog Scale (VAS) pain intensity score in participants aged 12 to less than 18 years [ Time Frame: Up to 96 hours ]
    The participant will be asked to draw a single line to indicate the current level of pain intensity on 100 mm long VAS. The scoring is the distance in millimeters across the scale with 0 mm is no pain and 100 mm is worst possible pain.

  9. Clinical Global Impression of Change (CGIC) [ Time Frame: Day 4 ]
    The investigator rated the participant's global improvement and satisfaction with the treatment on a 7-point scale with 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. Higher scores indicate worsening.

  10. Patient Global Impression of Change (PGIC) [ Time Frame: Day 4 ]
    Participants verbally rated their impression of overall status on a 7-point scale with 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. Higher scores indicate worsening.

  11. Time to receive first and second patient or nurse controlled analgesia after the first dose of IMP [ Time Frame: Up to 96 hours ]
  12. Time from first dose of IMP until treatment discontinuation due to lack of efficacy [ Time Frame: Up to 72 hours ]


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Informed consent, and if applicable assent, given according to local regulations.
  2. Male or female participant aged from birth (37 weeks gestational age) to less than 18 years.
  3. A female subject must be pre-menarchal, or surgically incapable of childbearing, or sexually abstinent, or if a female subject is sexually active, then she must be practicing an effective method of birth control (e.g., prescription hormonal contraceptives, intra-uterine devices used according to the product's instruction, double-barrier methods) before trial entry and throughout the trial.
  4. A female subject must have a negative pregnancy test if aged 12 years or older, or is post-menarchal, or is sexually active.
  5. Participant has undergone surgery (other than brain surgery or gastrointestinal surgery expected to affect the absorption of tapentadol [in the investigator's judgment]) that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment for at least 24 hours after first dose of Investigational Medicinal Product. Participants must remain hospitalized until the End of Treatment Visit.
  6. Participant has received post-operative morphine or hydromorphone by NCA (Nurse Controlled Analgesia)/PCA (Patient Controlled Analgesia), with or without a background infusion of the same opioid, according to standard of care prior to allocation/randomization to Investigational Medicinal Product and participant is expected to require this morphine or hydromorphone by NCA/PCA after starting Investigational Medicinal Product.
  7. Participant is able to tolerate liquids at the time of allocation/randomization to Investigational Medicinal Product.

Exclusion Criteria:

  1. Participant, parent or the legal representative is an employee of the investigator or trial site, with direct involvement in the proposed trial or other trials under the direction of that investigator or trial site, or family member of the employees or the investigator.
  2. Participant has been previously exposed to tapentadol.
  3. Participant has received an experimental drug or used an experimental medical device within 28 days before allocation/randomization to IMP, or within a period less than 10 times the drug's half-life, whichever is longer.
  4. Participant has a history or current condition of any one of the following:

    • Non-febrile seizure disorder.
    • Epilepsy.
    • Serotonin syndrome.
    • Traumatic or hypoxic brain injury, brain contusion, stroke, transient ischemic attack, intracranial hematoma, post-traumatic amnesia, brain neoplasm, or episode(s) of unconsciousness of more than 24 hours.
  5. Participant has a history or current condition of any one of the following:

    • Moderate to severe renal or hepatic impairment.
    • Abnormal pulmonary function or clinically relevant respiratory disease (e.g., acute or severe bronchial asthma, hypercapnia).
  6. Participant has a concomitant disease or disorder (e.g., endocrine, metabolic, neurological, psychiatric, infection, febrile seizure, paralytic ileus) that in the opinion of the investigator may affect or compromise participant safety during the study participation.
  7. Participant has history of suicidal ideation or behavior.
  8. Participant is obese in the investigator's judgment. Obesity can be determined based on appropriate BMI charts or tables; e.g., a BMI above the 97th percentile for children based on the World Health Organization growth charts or the participant's weight is less than 2500 gram.
  9. Participant has a clinically relevant history of hypersensitivity, allergy, or contraindication to the supplemental opioid analgesic medication or tapentadol, or the excipients, or naloxone.
  10. Participant is not able to understand and comply with the protocol as appropriate for the age of the participant or participant is cognitively impaired in the investigator's judgment such that they cannot comply with the protocol
  11. Participant has a history of alcohol and/or substance abuse in the investigator's judgment based on participant's history and physical examination.
  12. Participant is taking prohibited concomitant medication.
  13. Participant has received a long-acting opioid for the treatment of pain following surgery within 6 hours of allocation/randomization to Investigational Medicinal Product.
  14. Participant has clinically relevant (in the investigator's judgment) abnormal values for clinical chemistry or hematology (local laboratory sample taken after surgery).

    - A participant is excluded if the:

    • Aspartate transaminase or alanine transaminase is greater 3-times upper limit of normal.
    • Total bilirubin is greater 2-times upper limit of normal (except if the cause is due to Gilbert's syndrome).
    • Glomerular filtration rate less than 60 mL/min.

    A subject aged from birth to less than 6 months old is excluded if:

    • Aspartate transaminase or alanine transaminase is >3-times upper limit of normal.
    • There is pathological jaundice in the opinion of the investigator.
    • Glomerular filtration rate (calculated according to Schwartz et al. 1984) is:

      • <20 mL/min/1.73 m2 for subjects <1 week postpartum.
      • <30 mL/min/1.73 m2 for subjects 1 week to 8 weeks post-partum.
      • <50 mL/min/1.73 m2 for subjects >8 weeks postpartum to <6 months old.
  15. Participant has:

    • Clinically relevant abnormal ECG.
    • Signs of pre-excitation syndrome.
    • Brugada's syndrome.
    • QT or corrected QT interval (QTc) interval >470 ms for children aged 6 years to less than 18 years old.
    • QT or QTc interval >460 ms for children aged from birth to less than 6 years old.
  16. Peri- or post-operative analgesia supplied by a continuous regional technique (e.g., nerve block, wound infiltration catheter) or subject controlled epidural analgesia that was terminated less than 6 hours before allocation/randomization to Investigational Medicinal Product.
  17. Participant has post-operative clinically unstable systolic and diastolic blood pressure, heart rate, respiratory depression, or clinically unstable upper or lower airway conditions (in the investigator's judgment), or a saturation of peripheral oxygen (SpO2) <92% at the time of randomization (allocation/randomization to Investigational Medicinal Product).
  18. Female participant is breast-feeding a child.
  19. Participant requires continuous positive airway pressure or mechanical ventilation, at the time of allocation to Investigational Medicinal Product.
  20. The mother of a newborn subject or the breastfeeding mother of a subject was administered a prohibited medication.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02081391


Contacts
Contact: Grünenthal Clinical Trials Helpdesk +49 241 569 3223 clinical-trials@grunenthal.com

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Sponsors and Collaborators
Grünenthal GmbH
Depomed
Investigators
Study Director: Grünenthal Study Director Grünenthal GmbH

Publications:
Responsible Party: Grünenthal GmbH
ClinicalTrials.gov Identifier: NCT02081391     History of Changes
Other Study ID Numbers: KF5503/65
2012-004359-35 ( EudraCT Number )
First Posted: March 7, 2014    Key Record Dates
Last Update Posted: December 12, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Information available on the Grünenthal Web Site
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
URL: http://www.grunenthal.com/r-d-vision-mission/clinical-trials/data-sharing-clinical-trials

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Grünenthal GmbH:
Acute Pain
Post-operative
Tapentadol
Opioid Treatment
Pediatric Participants

Additional relevant MeSH terms:
Acute Pain
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Pharmaceutical Solutions
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents