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An Open-label Trial, Enrolling Subjects Aged 6 Years to Less Than 18 Years Suffering From Pain Requiring Prolonged Release Opioid Treatment, to Evaluate the Safety and Efficacy of Tapentadol PR Versus Morphine PR, Followed by an Open-label Extension.

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ClinicalTrials.gov Identifier: NCT02151682
Recruitment Status : Active, not recruiting
First Posted : May 30, 2014
Last Update Posted : November 29, 2017
Sponsor:
Information provided by (Responsible Party):
Grünenthal GmbH

Brief Summary:

Tapentadol has already been studied in adults. This study is needed to find out if tapentadol works and is safe to use in children and adolescents with long-term pain.

During the first 2 weeks of the study (Part 1), participants will be given either tapentadol or morphine prolonged-release tablets. Assignment will be done randomly (like tossing a coin). The participant and the caregiver will know which medication they are taking. The primary endpoint is based on data collected in Part 1 of this trial.

If eligible and willing, participants from Part 1 can enter a 12 month follow-up period (Part 2). In Part 2 of this trial participants will be treated with tapentadol prolonged release tablets or with the standard of care (observation arm).


Condition or disease Intervention/treatment Phase
Pain Drug: Tapentadol prolonged release Drug: Morphine prolonged release Phase 2 Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 73 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Trial, Enrolling Subjects Aged 6 Years to Less Than 18 Years Suffering From Pain Requiring Prolonged Release Opioid Treatment, to Evaluate the Safety and Efficacy of Tapentadol PR Versus Morphine PR, Followed by an Open-label Extension.
Actual Study Start Date : December 9, 2014
Actual Primary Completion Date : October 18, 2017
Estimated Study Completion Date : November 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Morphine prolonged release
10 mg or 30 mg tablets taken orally twice daily. Dose based on participant weight. The dose must not exceed a total of 200 mg per day for participants weighing 55 kg or more.
Drug: Morphine prolonged release
Participants aged from 6 years to less than 18 years with body weight less than 22.5 kg (but more than 17.5 kg) will start on 10 mg of morphine orally twice daily during the first 24 hours and then and then if necessary gradually stepwise increase the dose.

Experimental: Tapentadol prolonged-release
25 mg and or 100 mg tablets taken orally. Dose based on participant weight. The dose must not exceed a total of 500 mg per day for participants weighing 55 kg or more.
Drug: Tapentadol prolonged release
Participants aged from 6 years to less than 18 years with body weight less than 22.5 kg (but more than 17.5 kg) will start on 25 mg of tapentadol orally (by mouth) twice daily during the first 24 hours and then if necessary gradually stepwise increase the dose.
Other Names:
  • Palexia®
  • Nucynta®
  • Yantil®

Tapentadol after morphine
Participants that were randomized to morphine in part 1 of the open-label period can continue with tapentadol in part 2 of the trial. Participants will be rotated to tapentadol prolonged release with 70% of the current morphine equivalent dose or lower.
Drug: Tapentadol prolonged release
Participants aged from 6 years to less than 18 years with body weight less than 22.5 kg (but more than 17.5 kg) will start on 25 mg of tapentadol orally (by mouth) twice daily during the first 24 hours and then if necessary gradually stepwise increase the dose.
Other Names:
  • Palexia®
  • Nucynta®
  • Yantil®

Tapentadol open-label extension
Participants that were randomized to tapentadol in part 1 of the open-label period can continue with tapentadol in part 2 of the trial. Participants will continue on the current dose and if necessary can modify their tapentadol prolonged release dosage.
Drug: Tapentadol prolonged release
Participants aged from 6 years to less than 18 years with body weight less than 22.5 kg (but more than 17.5 kg) will start on 25 mg of tapentadol orally (by mouth) twice daily during the first 24 hours and then if necessary gradually stepwise increase the dose.
Other Names:
  • Palexia®
  • Nucynta®
  • Yantil®

No Intervention: Observation period after tapentadol in part 1
Participants not completing Part 1 can enter the Observation Period.
No Intervention: Observation period after morphine in part 1
Participants not completing Part 1 can enter the Observation Period.



Primary Outcome Measures :
  1. Binary variable "responder". [ Time Frame: up to Day 14 (End of Part 1) ]

    A participant is defined as responder if both of the following criteria are met:

    • Completion of the 14-day Treatment Period (Part 1).
    • One of the following calculated from the scheduled pain assessments ("pain right now") documented during the last 3 days of the Treatment Period:

      • Average pain less than 50 on a visual analog scale (VAS) for subjects aged 12 years to less than 18 years; or less than 5 on the Faces Pain Scale-revised (FPS-R) for subjects aged 6 years to less than 12 years.
      • Average reduction from baseline of pain greater than and equal to 20 on a VAS for subjects aged 12 years to less than 18 years; or greater and equal to 2 on the FPS-R for subjects aged 6 years to less than 12 years.

    The proportion of participants classified as responders will be assessed and compared between the treatment groups.



Secondary Outcome Measures :
  1. Constipation [ Time Frame: Day 1; Day 14 (End of Part 1) ]
    Constipation will be assessed using the modified constipation assessment scale (CAS). This is an 8-item questionnaire where the observer will score constipation on a nominal scale (no problem, some problem or severe problem). The response to an item could also be scored as "unable to assess".

  2. Tolerability [ Time Frame: Day 1 (Start of Part 1); Day 379 (End of Part 2) ]
    Tolerability will be assessed by the number and type of adverse events and adverse drug reactions by treatment group during the different trial periods, on a participant and event level.


Other Outcome Measures:
  1. Change in pain intensity in the open-label, active-controlled treatment period [ Time Frame: Baseline; Day 14 (End of Part 1) ]

    Pain Intensity will be assessed by scoring "pain right now" twice daily. "Pain right now" will be scored by every participant using the Visual Analog Score (VAS) as well as the Faces Pain Scale-Revised (FPS-R) at each time point in an electronic diary.

    The pain intensity will first be documented using the VAS and directly thereafter the FPS-R. If required, pain intensity diary entry maybe assisted by the legal guardian or a health care provider.

    The FPS-R is a self-reported 6 point scale ranging from "no pain" to "very much pain". Facial representations are used to indicate how much the pain hurts.


  2. Change in pain intensity in the tapentadol open-label extension period [ Time Frame: Day 15; Day 379 (End of Part 2) ]

    Pain Intensity will be assessed by scoring "pain right now" twice daily. "Pain right now" will be scored by every participant using the Visual Analog Score (VAS) as well as the Faces Pain Scale-Revised (FPS-R) at each time point.

    In this part of the trial the pain intensity will first be documented using the VAS and directly thereafter the FPS-R. If required, pain intensity diary entry maybe assisted by the legal guardian or a health care provider.

    Pain intensity on the VAS will be scored by the participant on a paper based 100 mm VAS ranging from "no pain" to "pain as bad as it could be".

    The FPS-R is a self-reported 6 point scale ranging from "no pain" to "very much pain". Facial representations are used to indicate how much the pain hurts.


  3. Use of rescue medication in the open-label, active-controlled treatment period [ Time Frame: Day 1; Day 14 (End of Part1) ]
    The number of doses of morphine oral solution used.

  4. Pharmacokinetic Concentrations of Tapentadol [ Time Frame: Day 1; Day 14 (End of Part1) ]
    Tapentadol concentrations will measured in participants in the tapentadol treatment arm.

  5. Pharmacokinetic Concentrations of Tapentadol-O-glucoronide [ Time Frame: Day 1; Day 14 (End of Part1) ]
    Tapentadol-O-glucuronide is a metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that can be more easily or quickly removed from the body. Tapentadol-O-glucoronide concentrations will be measured.

  6. Palatability of study medication [ Time Frame: Day 8 ]
    Palatability will be determined by asking the participant "How does the medication taste". The participant will be requested to give a score on a 5 point hedonic faces rating scale. The response can range from really bad to really good.

  7. Palatability of study medication [ Time Frame: Day 14 ]
    Palatability will be determined by asking the participant "How does the medication taste". The participant will be requested to give a score on a 5 point hedonic faces rating scale. The response can range from really bad to really good.

  8. Acceptability of study medication [ Time Frame: Day 8 ]
    Acceptability will be determined by asking the participant "Swallowing the medication is...". The participant will be requested to give a score on a 5 point hedonic faces rating scale. The response can range from really difficult to really easy.

  9. Acceptability of study medication [ Time Frame: Day 14 ]
    Acceptability will be determined by asking the participant "Swallowing the medication is...". The participant will be requested to give a score on a 5 point hedonic faces rating scale. The response can range from really difficult to really easy.

  10. Constipation [ Time Frame: Day 15; Day 379 (End of Part 2) ]
    Constipation will be assessed using the modified constipation assessment scale (CAS). This is an 8-item questionnaire where the observer will score constipation on a nominal scale (no problem, some problem or severe problem). The response to an item could also be scored as "unable to assess".

  11. Subjective opiate withdrawal scale [ Time Frame: Day 386 ]
    Each participant will be requested to score 15 items on the 16 item questionnaire for 7 days after discontinuation of treatment. Opiate withdrawal symptoms will be assessed using the subjective opiate withdrawal scale (SOWS) questionnaire. The participants rate their experience on specific questions on a 0 (not at all) to 4 (extremely). The minimum score is 0, the maximum score is 64. THe SOWS is designed to reflect common motoric, autonomic, musculoskeletal and psychic signs and symptoms of opiate withdrawal.

  12. Time to discontinuation. [ Time Frame: Day 1; Day 379 ]

    In the event that more than 10% of participants discontinue in one of the 3 study medication treatment groups a survival analysis will be performed.

    The discontinuation from study medication due to lack of efficacy and due to treatment emergent events will be analyzed for both the tapentadol prolonged release and morphine prolonged release treatment arms in part 1 of the trial, as well as for tapentadol prolonged release treatment in part 2 of the trial.




Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Part 1 - Randomized to open-label, active comparator controlled treatment

Participants are eligible for the trial at if all the following apply:

  • Informed consent (if applicable assent) obtained.
  • Male or female participant at least 6 years of age at the Enrollment Visit and less than 18 years of age on Day 14.
  • Participant has an underlying long-term pain condition (e.g., cancer, chronic disease, planned or performed surgery) that is, according to the judgment of the investigator, expected to require a twice-daily prolonged release opioid treatment until at least the end of the 14-day Treatment Period.
  • Participant can swallow tablets of appropriate size.
  • Participant is able to participate in the trial as planned and willing to comply with the requirements of the protocol including refraining from drinking beverages containing alcohol and recreational intake of drugs while on study medication.

Participants must satisfy the following criteria before allocation to treatment:

  • Less than 18 years of age.
  • No opioid intake or last calculated morphine equivalent dose of less than 3.5 mg/kg per day.
  • Participant has a body weight of at least 17.5 kg.
  • If a female of childbearing potential (post menarchal and not surgically incapable of childbearing) and sexually active, must practice an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double barrier method, contraceptive patch) before allocation to study medication until the end of intake of study medication.
  • If a female and post menarchal or older than 12 years, has a negative urine pregnancy test on the day before or on the day of allocation to study medication.

Part 2

Inclusion criteria for the Tapentadol Open-label extension period:

  • Participant has completed the 14-day Treatment Period.
  • Participant is still in need of prolonged release opioid treatment.
  • Participant does not meet any of the compulsory discontinuation criteria.

Exclusion Criteria:

Participants are not eligible for the trial if any of the following apply.

The following will be checked at enrollment:

  • Has been previously enrolled in this trial or a previous trial with tapentadol.
  • Has a clinically relevant history of hypersensitivity, allergy, or contraindication to morphine or tapentadol or any ingredient, including galactose intolerance (see investigator's brochure for tapentadol PR and summary of product characteristics for morphine PR), or naloxone.
  • History or current condition of any one of the following:

    • Seizure disorder or epilepsy.
    • Serotonin syndrome.
    • Traumatic or hypoxic brain injury, brain contusion, stroke, transient ischemic attack, intracranial hematoma, posttraumatic amnesia, brain neoplasm, or episode(s) of more than 24 hours duration of unconsciousness.
  • 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)
    • Complex regional pain syndrome.
    • A pain indication with a strong psycho-somatic component that, in the judgment of the investigator, is unlikely to respond to opioids.
  • History of alcohol or drug abuse in the investigator's judgment, based on history and physical examination. Drugs of abuse detected in urine screen unless explained by allowed concomitant medication
  • Participant has:

    • A clinically relevant abnormal electrocardiogram.
    • Signs of pre-excitation syndrome.
    • Brugada's syndrome.
    • QT or QTcF (Fridericia) interval greater than 470 ms.
  • Any surgery scheduled during the first 14 days of the trial that is expected to require post-surgical intensive care unit (ICU) treatment, or that requires post-surgical parenteral pain-treatment, or may, affect the safety of the participant.
  • Participant is not able to understand and comply with the protocol as appropriate for the age of the subject or subject is cognitively impaired in the investigator's judgment such that they cannot comply with the protocol.
  • Participant, parent or the legal representative is an employee of the investigator or trial site, with direct involvement in the proposed trial or other studies under the direction of that investigator or trial site, or family member of the employees or the investigator.

The following will be checked at the enrollment and the allocation visits:

  • Has a concomitant disease or disorder (e.g., endocrine, metabolic, neurological, psychiatric, infection) that in the opinion of the investigator may affect or compromise subject safety during the trial participation.
  • Pancreatic/biliary tract disease (e.g., pancreatitis) or paralytic ileus.
  • Intake of forbidden concomitant medication/use of forbidden therapies (see synopsis section Concomitant medications/therapies).
  • Female participant is breastfeeding a child.

The following will be checked at the allocation to treatment visit:

  • Has received a drug or used a medical device not approved for human use within 30 days prior to visit.
  • Based on data from the local laboratory, one or more of:

    • Total serum bilirubin greater than 2.0 mg/dL.
    • Serum albumin less than 2.8 g/dL.
    • Aspartate transaminase or alanine transaminase greater than 5 times upper limit of normal.
  • Based on data from the local laboratory, creatinine clearance less than 30 mL/min per 1.73 m2 (calculated according to a formula that is appropriate for the respective age group).

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): NCT02151682


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Sponsors and Collaborators
Grünenthal GmbH
Investigators
Study Director: Director Clinical Trials Grünenthal GmbH

Responsible Party: Grünenthal GmbH
ClinicalTrials.gov Identifier: NCT02151682     History of Changes
Other Study ID Numbers: KF5503-66
2012-004360-22 ( EudraCT Number )
U1111-1154-4572 ( Other Identifier: WHO )
First Posted: May 30, 2014    Key Record Dates
Last Update Posted: November 29, 2017
Last Verified: November 2017

Keywords provided by Grünenthal GmbH:
chronic pain
opioid

Additional relevant MeSH terms:
Analgesics, Opioid
Morphine
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents