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

• ClinicalTrials.gov Identifier: NCT02151682
• Recruitment Status: Completed
• First Posted: May 30, 2014
• Results First Posted: September 12, 2019
• Last Update Posted: September 12, 2019
• Sponsor: Grünenthal GmbH
• Information provided by (Responsible Party): Grünenthal GmbH

Study Description

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.

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

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 73 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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)
• 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: April 29, 2015
• Actual Primary Completion Date: October 18, 2017
• Actual Study Completion Date: October 15, 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Morphine prolonged-release (Part 1); 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
Experimental: Tapentadol prolonged-release (Part 1); 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; Other Names: Palexia®; Nucynta®; Yantil®
Experimental: Tapentadol in Part 2 after Tapentadol or Morphine in Part 1; 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; Other Names: Palexia®; Nucynta®; Yantil®
No Intervention: Observation Period after Tapentadol in Part 1; 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; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Classified as Responder (Part 1) [ Time Frame: From Day 1 up to Day 14 (End of 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.

Secondary Outcome Measures :

1. Extent of Constipation (Part 1) [ Time Frame: From Day 1 to Day 14 (End of 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.

2. Tolerability Over the Complete Trial Period [ Time Frame: Part 1: Day 1 (Start of Part 1) to Day 14; Part 2: Day 15 to Day 379 (End of Part 2) ]

   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.

Other Outcome Measures:

1. Change in Pain Intensity in the Open-label, Active-controlled Treatment Period (Part 1) [ Time Frame: From Baseline up to Day 14 (End of Part 1) or early discontinuation ]

   Pain intensity was assessed by scoring "Pain right now" twice daily up to Day 14 by every participant using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) in an electronic diary. Pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity diary entry could be assisted by the legal guardian or a health care provider.

   The VAS is scored from 0, equivalent to "no pain", to 100, equivalent to "pain as bad as it could be".

   The FPS-R is a validated self-reported 6-point scale with 0 representing "no pain" and 10 representing "very much pain". Facial representations were used to indicate how much the pain hurts.

   The "pain right now" scores at baseline (last evaluation before starting IMP) and the mean of last 6 assessments collected up to the time point of last IMP intake in Part 1 (i.e., Day 14 or the day of early discontinuation) were used for the calculation of the change in pain intensity from baseline.

2. Change in Pain Intensity in the Tapentadol Open-label Extension Period (Part 2) [ Time Frame: From Day 15 to Day 379 (End of Part 2) ]

   Pain intensity was assessed by scoring "Pain right now" using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) at each visit. The pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity assessments could be assisted by the legal guardian or a health care provider.

   The VAS is scored from 0, equivalent to "no pain", to 100, equivalent to "pain as bad as it could be". The FPS-R is a validated self-reported 6-point scale with 0 representing "no pain" and 10 representing "very much pain". Facial representations were used to indicate how much the pain hurts.

   The "pain right now" score at the tapentadol baseline (last evaluation before or at Day 15) and at the last assessment for those subjects who completed the 12 months treatment of Part 2 were used for the calculation of the change in pain intensity from the tapentadol baseline.

3. Use of Rescue Medication in the Open-Label, Active-controlled Treatment Period (Part 1) [ Time Frame: From Day 1 up to Day 14 (End of Part 1) ]

   Due to an overall low intake of rescue medication, it was not appropriate to present the number of doses of oral morphine solution used at different dose levels of investigational medicinal product (IMP) but the average daily dose (milligrams per kilogram body weight) for the treatment period and a modified average daily dose. Average daily dose and modified average daily dose were both calculated based on drug accountability.

   For the modified average daily doses, implausible values were excluded from the analysis, i.e., the amount of rescue medication that was lost due to a broken bottle was excluded from the analysis and negative amounts of rescue medication intakes due to measurement inaccuracies for bottle weights were considered as no intake.

4. Serum Concentrations of Tapentadol (Part 1) [ Time Frame: From Day 1 to Day 14 (End of Part 1) ]

   Tapentadol serum concentrations were measured in participants in the tapentadol treatment arm (Part 1).

   All participants who had quantifiable serum concentrations during the Treatment Period were included in the descriptive pharmacokinetic analysis. Data from participants who vomited within 6 hours of administration of IMP during the Treatment Period were carefully assessed to decide if the data should be included in the pharmacokinetic analysis.

5. Serum Concentrations of Tapentadol-O-glucuronide (Part 1) [ Time Frame: From Day 1 to Day 14 (End of Part1) ]

   Tapentadol-O-glucuronide is a metabolite of tapentadol. The body transforms tapentadol into its metabolites so that it can be more easily/quickly removed from the body. Tapentadol-O-glucuronide serum concentrations were measured in participants who received tapentadol PR in Part 1.

   All participants who had quantifiable serum concentrations were included in the descriptive pharmacokinetic analysis. Data from participants who vomited within 6 hours of administration of IMP during Part 1 were carefully assessed to decide if they should be included in the pharmacokinetic analysis.

6. Palatability of Study Medication (Part 1, Day 8) [ Time Frame: Day 8 (Part 1) ]
   Palatability was determined in Part 1 by asking the participant "How does the medication taste". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really bad to really good.
7. Palatability of Study Medication (Part 1, Day 14) [ Time Frame: Day 14 (Part 1) ]
   Palatability was determined in Part 1 by asking the participant "How does the medication taste". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really bad to really good.
8. Acceptability of Study Medication (Part 1, Day 8) [ Time Frame: Day 8 (Part 1) ]
   Acceptability of the study medication was determined in Part 1 by asking the participant "Swallowing the medication is...". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really difficult to really easy.
9. Acceptability of Study Medication (Part 1, Day 14) [ Time Frame: Day 14 (End of Part 1) ]
   Acceptability of the study medication was determined in Part 1 by asking the participant "Swallowing the medication is...". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really difficult to really easy.
10. Extent of Constipation (Part 2) [ Time Frame: From baseline (Day 15 or switch) to last assessment (up to Day 379 of Part 2) ]

    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 baseline to last assessment indicates a worsening, a negative change an improvement.

11. Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS) [ Time Frame: From Day 1 to Day 386 (End of Part 2 + 7 days) ]

    Opiate withdrawal symptoms were assessed using the Subjective Opiate Withdrawal Scale (SOWS) questionnaire. The SOWS is designed to reflect common motoric, autonomic, musculoskeletal, and psychic signs and symptoms of opiate withdrawal. Each participant was requested to rate the first 15 items of the 16-item questionnaire for 7 days after last IMP intake. Participants rated the intensity of specific signs and symptoms on a scale of 0 (not at all) to 4 (extremely). The minimum overall score is 0, the maximum score is 64.

    SOWS Total Score at baseline (i.e., for Part 1 = Day 14-17, for Part 2 = Day 352-380, or the day after an early termination visit (Part 1/2)), and changes from baseline 2-7 days after last intake of IMP in Part 1 (= up to Day 23) and in Part 2 (= up to Day 386) are presented.

12. Time to Discontinuation (Lack of Efficacy) in Part 1 [ Time Frame: From first day in Part 1 (Day 1) to last day in Part 1 ]
    The time to discontinuation from IMP due to lack of efficacy was planned to be analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the trial. However, no participant was reported with early discontinuation from IMP due to lack of efficacy. Consequently, no time to discontinuation can be reported.
13. Time to Discontinuation (Lack of Efficacy) in Part 2 [ Time Frame: From first day in Part 2 (Day 15) to last day in Part 2 (Day 379) ]
    The time to discontinuation from IMP due to lack of efficacy was analyzed for tapentadol PR treatment in Part 2 of the trial.
14. Time to Discontinuation (Treatment Emergent Adverse Events) in Part 1 [ Time Frame: From first day in Part 1 (Day 1) to last day in Part 1 (Day 14) ]

    The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the study.

    Note that no participant discontinued due to a TEAE in the morphine PR arm, and 2 participants in the tapentadol PR arm.

15. Time to Discontinuation (Treatment Emergent Adverse Events) in Part 2 [ Time Frame: From first day in Part 2 (Day 15) to last day in Part 2 (Day 379) ]
    The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for tapentadol PR treatment in Part 2 of the study.
16. Time to First Intake of Rescue Medication in the Open-label, Active-controlled Treatment Period (Part 1) [ Time Frame: From Day 1 up to Day 14 (End of Part 1) ]

    Morphine oral solution could be given during Part 1 as rescue medication in both treatment groups. The dose per rescue medication intake was 1/6 of the total daily dose of the scheduled tapentadol or morphine PR intakes. Rescue medication administration times and doses were recorded.

    18 Participants in the morphine PR group and 27 participants in the tapentadol PR group had no documented intake of rescue medication between Day 1 and Day 14.

    Summary statistics were calculated based on participants with any intake, i.e., those that took at least 1 dose of rescue medication. The mean (standard deviation) time (hours) to first dose of rescue medication following the first dose of the IMP (on Day 1) is presented.

Eligibility Criteria

• 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 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).

Contacts and Locations

Locations

Belgium

BE001

Leuven, Belgium, 3000

Bulgaria

BG005

Pleven, Bulgaria, 5800

BG004

Plovdiv, Bulgaria, 4001

BG001

Sofia, Bulgaria, 1606

BG006

Sofia, Bulgaria, 1606

Chile

CL004

Santiago, Chile, 7500996

CL001

Valparaíso, Chile, 2341131

France

FR008

Amiens, France, 80054

FR004

Brest, France, 29609

FR002

Lille, France, 59020

FR006

Lyon, France, 69008

FR005

Nice, France, 06200

FR001

Vandoeuvre les Nancy, France, 54500

FR003

Villejuif Cedex, France, 94805

Germany

DE001

Homburg, Germany, 66421

Hungary

HU001

Budapest, Hungary, 1094

Italy

IT003

Turin, Italy, 10126

Portugal

PT001

Braga, Portugal, 4710-243

PT002

Porto, Portugal, 4200-319

Spain

ES003

Valladolid, Spain, 47005

United Kingdom

GB005

Leeds, United Kingdom, LS1 3EX

GB003

Manchester, United Kingdom, M13 9WL

GB006

Sheffield, United Kingdom, S10 2TH

Sponsors and Collaborators

Grünenthal GmbH

Investigators

• Study Director: Director Clinical Trials; Grünenthal GmbH

  Study Documents (Full-Text)

Documents provided by Grünenthal GmbH:

Study Protocol  [PDF] July 27, 2017

Statistical Analysis Plan  [PDF] February 13, 2018

More Information

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT02151682
• Other Study ID Numbers: KF5503-66; 2012-004360-22 ( EudraCT Number ); U1111-1154-4572 ( Other Identifier: WHO )
• First Posted: May 30, 2014
• Results First Posted: September 12, 2019
• Last Update Posted: September 12, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Information available on the Grünenthal Web Site (see URL below for details)
• 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: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Grünenthal GmbH:

chronic pain; opioid

Additional relevant MeSH terms:

Morphine; Tapentadol; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Adrenergic Agents; Neurotransmitter Agents