| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pain requiring prolonged release opioid treatment. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Disease or a condition that causes pain that is lasting a long time. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049475 |
| E.1.2 | Term | Chronic pain |
| E.1.2 | System Organ Class | 100000023314 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The trial objectives for Part 1 of the trial are:
• To assess the 14-day safety and efficacy of tapentadol PR (prologed release) in comparison to morphine PR in subjects aged from 6 years to less than 18 years suffering from long-term pain requiring prolonged release opioid treatment.
• To evaluate the pharmacokinetic profile of tapentadol and its major metabolite tapentadol-O-glucuronide after multiple doses of tapentadol PR tablets.
The trial objective for Part 2 of the trial is:
•To describe the long term safety profile covering up to a 12-month period with treatment of tapentadol PR taken twice daily (Tapentadol Period) in subjects aged 6 years or older suffering from long-term pain requiring prolonged release opioid treatment, or in subjects without tapentadol treatment (Observation Period) aged 6 years or older who have received at least 1 dose of investigational medicinal product (IMP). |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects are eligible for the trial at if all the following apply:
1. Informed consent/(if applicable) assent obtained.
2. Male or female subject at least 6 years of age at the Enrollment Visit and less than 18 years of age on the predicted day of Visit VE.
3. Subject has an underlying long-term pain condition 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 (Visit VE).
4. Subject can swallow tablets of appropriate size.
5. Subject 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 IMP.
Subjects must satisfy the following criteria at Visit V2:
6. Less than 18 years of age on the planned day of Visit VE.
7. No opioid intake or last calculated morphine equivalent dose at day of allocation of less than 3.5 mg/kg per day.
8. Subject has a body weight of at least 17.5 kg.
9. 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 IMP until the end of intake of IMP.
10. 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 IMP.
Inclusion criteria for the Tapentadol Period (Part 2):
17. Subject has completed the 14-day Treatment Period.
18. Subject is still in need of prolonged release opioid treatment.
19. Subject does not meet any of the compulsory discontinuation criteria (described in Section 9.3.1 of the body of the protocol).
|
|
| E.4 | Principal exclusion criteria |
Subjects are not eligible for the trial if any of the following apply:
The following will be checked at Visit V1:
1. Has been previously enrolled in this trial or a previous trial with tapentadol.
2. 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.
3. 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.
4. 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.
5. 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.
6. Subject has:
• A clinically relevant abnormal ECG.
• Signs of pre-excitation syndrome.
• Brugada’s syndrome.
• QT or QTcF (Fridericia) interval greater than 470 ms.
7. Any surgery scheduled during Part 1 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, in the opinion of the investigator, affect the safety of the subject.
8. Subject 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.
9. Subject, 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 Visit V1 and Visit V2:
10. 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.
11. Pancreatic/biliary tract disease (e.g., pancreatitis) or paralytic ileus.
12. Intake of forbidden concomitant medication/use of forbidden therapies.
13. Female subject breast-feeding a child.
The following will be checked at Visit V2:
14. Has received a drug or used a medical device not approved for human use within 30 days prior to Visit V2.
15. 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.
16. 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).
17. [criteria deleted] |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is a binary variable “responder”. A subject 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 subjects classified as responders will be assessed and compared between the treatment groups. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Part 1 primary analysis of the 14 day treatment Period in Part 1 of the trial. |
|
| E.5.2 | Secondary end point(s) |
Part 1:
• Constipation as assessed by changes from baseline (Visit V2) of total scores for the modified CAS.
Part 1 and Part 2:
• Tolerability as assessed by the number and type of adverse events and adverse drug reactions by treatment group during the different trial periods, on a subject and event level.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1
Constipation using the Modified Constipation Assessment Scale for Pediatrics: change from Visit V2 (allocation) up to Day 16.
Part 1 and Part 2
Tolerability, number and type of adverse events: from Visit V2 (Part 1) up to Visit F12M (end of Part 2 - up to 54 weeks after first dose in Part 1) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Morphine randomized subjects can switch to open label extension period with tapentadol in Part 2 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Morphine prolonged release tablets |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 51 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Bulgaria |
| Chile |
| Colombia |
| Croatia |
| France |
| Germany |
| Hungary |
| Italy |
| Mexico |
| Netherlands |
| Portugal |
| Slovakia |
| Slovenia |
| Spain |
| Switzerland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
Print
