A Study to Look at Tapentadol Tablets in Children and Adolescents in Pain

Study Overview
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Brief Summary
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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.

Detailed Description
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During the first 2 weeks of the study (Part 1), participants were given either tapentadol or morphine prolonged-release (PR) tablets. Assignment was done randomly (like tossing a coin). The participant and the caregiver knew which medication the child was taking. The primary endpoint was based on data collected in Part 1 of this study. If eligible and willing, participants from Part 1 could enter a 12 month follow-up period (Part 2). In Part 2 of this study, participants were either treated with tapentadol PR tablets or entered observations arms where they were not treated at all or with standard of care.

Official Title
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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

Conditions
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Pain

Intervention / Treatment
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* Drug: Tapentadol prolonged release
* Drug: Morphine prolonged release


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1 - Randomized to open-label, active comparator controlled treatment Participants were eligible for the study at enrollment if all the following applied: 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 study 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 had to 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 were not eligible for the study if any of the following applied. The following was checked at enrollment: Has been previously enrolled in this study or a previous study 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 prolonged-release [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 corrected QT (QTcF, Fridericia) interval greater than 470 ms. Any surgery scheduled during the first 14 days of the study 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 participant or participant 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 study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, or family member of the employees or the investigator. The following was 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 participant safety during the study 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 was 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).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There were 2 arms in Part 1: Randomization was carried out in blocks and in a 2:1 ratio (tapentadol PR to morphine PR). Participants were stratified using interactive response technology: by age group (6 years to less than 12 years and 12 years to less than 18 years, at the second visit [Allocation Visit]) so that at least 25% of participants were in the younger age group, and by underlying pain condition (cancer/non-cancer-related pain). There were 4 arms in Part 2: The investigators/participants decided if participants from Part 1 switched to or continued on tapentadol PR (tapentadol arm) or if they received no treatment/standard of care treatment if needed (2 direct observation arms following treatment in Part 1 and 1 observation arm after initial treatment with tapentadol in Part 2).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morphine prolonged-release (Part 1)<br>10 milligram (mg) or 30 mg tablets were taken orally twice daily. Starting doses varied from 10 to 40 mg morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day. | Drug: Morphine prolonged release<br> <br> |
| Experimental: Tapentadol prolonged-release (Part 1)<br>25 mg or 100 mg tablets were taken orally twice daily. Starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day. | Drug: Tapentadol prolonged release<br> <br> * Other names: Yantil®;|
| Experimental: Tapentadol in Part 2 after Tapentadol or Morphine in Part 1<br>Participants on tapentadol PR in Part 1 of the study continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants who were randomized to morphine PR in Part 1 of the study were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily. | Drug: Tapentadol prolonged release<br> <br> * Other names: Yantil®;|
| No Intervention: Observation Period after Tapentadol in Part 1<br>Participants who completed tapentadol PR in Part 1 of the study or discontinued tapentadol treatment early in Part 1 could continue directly in the observation period in Part 2 for up to 12 months (with standard-of-care treatment if needed). | |
| No Intervention: Observation Period after Morphine in Part 1<br>Participants who completed morphine PR treatment in Part 1 of the study or discontinued early from morphine treatment in Part 1 could continue directly in the observation period in Part 2 (with standard-of-care treatment if needed). | |
| No Intervention: Observation Period after Tapentadol in Part 2<br>Participants who completed tapentadol PR or morphine PR treatment in Part 1 of the study could enter the Observation Period for up to 12 months (with standard-of-care treatment if needed) after they had discontinued from tapentadol PR treatment in Part 2. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Classified as Responder (Part 1) | The proportion of participants classified as responders was assessed and compared between the treatment groups. A participant was defined as responder if both of the following criteria were 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, range 0 [no pain] to 100 [pain as bad as it could be]) for participants aged 12 years to less than 18 years; or less than 5 on the Faces Pain Scale-revised (FPS-R, range 0 [no pain] and 10 [very much pain]) for participants aged 6 years to less than 12 years. Average reduction from baseline of pain greater than or equal to 20 on a VAS for participants aged 12 years to less than 18 years; or greater than or equal to 2 on the FPS-R for participants aged 6 years to less than 12 years. | From Day 1 up to Day 14 (End of Part 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extent of Constipation (Part 1) | Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no Problem [score 0], some problem [score 1] or severe Problem [score 2]). The response to an item could also be scored as unable to assess. The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from Day 1 to Day 14 indicates a worsening, a negative change an improvement. | From Day 1 to Day 14 (End of Part 1) | 
| Tolerability Over the Complete Trial Period | Tolerability was assessed by the number of participants with exactly 1 to more than 5 treatment emergent adverse events (TEAE) by treatment group during the different trial periods, on a participant level. In addition, tolerability was assessed by the number of participants with TEAEs which were considered by the investigator to be at least possibly related to the treatment the participant received. | Part 1: Day 1 (Start of Part 1) to Day 14; Part 2: Day 15 to Day 379 (End of Part 2) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic pain, opioid