Clinical trial NCT02151682: A Study to Look at Tapentadol Tablets in Children and Adolescents in Pain
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Pain
Keywords: chronic pain
opioid
Lead sponsor: Grünenthal GmbH
Sponsor class: INDUSTRY
First posted: 2014-05-30
Enrollment: 73
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: TREATMENT

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.

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.

Eligibility 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).

Primary outcomes:
measure: Number of Participants Classified as Responder (Part 1)
timeFrame: From Day 1 up to Day 14 (End of Part 1)
Secondary outcomes:
measure: Extent of Constipation (Part 1)
timeFrame: From Day 1 to Day 14 (End of Part 1)
measure: Tolerability Over the Complete Trial Period
timeFrame: Part 1: Day 1 (Start of Part 1) to Day 14; Part 2: Day 15 to Day 379 (End of Part 2)
Other outcomes:
measure: Change in Pain Intensity in the Open-label, Active-controlled Treatment Period (Part 1)
timeFrame: From Baseline up to Day 14 (End of Part 1) or early discontinuation
measure: Change in Pain Intensity in the Tapentadol Open-label Extension Period (Part 2)
timeFrame: From Day 15 to Day 379 (End of Part 2)
measure: Use of Rescue Medication in the Open-Label, Active-controlled Treatment Period (Part 1)
timeFrame: From Day 1 up to Day 14 (End of Part 1)
measure: Serum Concentrations of Tapentadol (Part 1)
timeFrame: From Day 1 to Day 14 (End of Part 1)
measure: Serum Concentrations of Tapentadol-O-glucuronide (Part 1)
timeFrame: From Day 1 to Day 14 (End of Part1)
measure: Palatability of Study Medication (Part 1, Day 8)
timeFrame: Day 8 (Part 1)
measure: Palatability of Study Medication (Part 1, Day 14)
timeFrame: Day 14 (Part 1)
measure: Acceptability of Study Medication (Part 1, Day 8)
timeFrame: Day 8 (Part 1)
measure: Acceptability of Study Medication (Part 1, Day 14)
timeFrame: Day 14 (End of Part 1)
measure: Extent of Constipation (Part 2)
timeFrame: From baseline (Day 15 or switch) to last assessment (up to Day 379 of Part 2)
measure: Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS)
timeFrame: From Day 1 to Day 386 (End of Part 2 + 7 days)
measure: Time to Discontinuation (Lack of Efficacy) in Part 1
timeFrame: From first day in Part 1 (Day 1) to last day in Part 1
measure: Time to Discontinuation (Lack of Efficacy) in Part 2
timeFrame: From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)
measure: Time to Discontinuation (Treatment Emergent Adverse Events) in Part 1
timeFrame: From first day in Part 1 (Day 1) to last day in Part 1 (Day 14)
measure: Time to Discontinuation (Treatment Emergent Adverse Events) in Part 2
timeFrame: From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)
measure: Time to First Intake of Rescue Medication in the Open-label, Active-controlled Treatment Period (Part 1)
timeFrame: From Day 1 up to Day 14 (End of Part 1)
Locations:
city: Leuven
country: Belgium
facility: BE001
city: Pleven
country: Bulgaria
facility: BG005
city: Plovdiv
country: Bulgaria
facility: BG004
city: Sofia
country: Bulgaria
facility: BG001
city: Sofia
country: Bulgaria
facility: BG006
city: Santiago
country: Chile
facility: CL004
city: Valparaíso
country: Chile
facility: CL001
city: Amiens
country: France
facility: FR008
city: Brest
country: France
facility: FR004
city: Lille
country: France
facility: FR002
city: Lyon
country: France
facility: FR006
city: Nice
country: France
facility: FR005
city: Vandoeuvre les Nancy
country: France
facility: FR001
city: Villejuif Cedex
country: France
facility: FR003
city: Homburg
country: Germany
facility: DE001
city: Budapest
country: Hungary
facility: HU001
city: Turin
country: Italy
facility: IT003
city: Braga
country: Portugal
facility: PT001
city: Porto
country: Portugal
facility: PT002
city: Valladolid
country: Spain
facility: ES003
city: Leeds
country: United Kingdom
facility: GB005
city: Manchester
country: United Kingdom
facility: GB003
city: Sheffield
country: United Kingdom
facility: GB006
Study officials:
affiliation: Grünenthal GmbH
name: Director Clinical Trials
role: STUDY_DIRECTOR
References: