| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Opioid tolerant paediatric patients with moderate to severe malignant and/or nonmalignant pain requiring opioid therapy. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pain due to cancer or other causes |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10002182 |
| E.1.2 | Term | Analgesia |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 primary objective is to characterize the safety of oxycodone HCl CR tablets in opioid tolerant pediatric patients aged 6 to 16 years, inclusive, with moderate to severe malignant and/or nonmalignant pain requiring opioid therapy. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to characterize the efficacy and provide additional pharmacokinetics (PK) data for a population PK model of oxycodone HCl CR tablets in opioid tolerant pediatric patients aged 6 to 16 years, inclusive, with moderate to severe malignant and/or nonmalignant pain requiring opioid therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male and female patient aged 6 to 16 years, inclusive, who are expected to require ongoing around-the-clock opioid treatment equivalent to at least 20 mg daily dose of oxycodone for at least 2 weeks for management of moderate to severe(based on the investigator’s judgment) malignant or nonmalignant pain;
2) Patients must be opioid tolerant, ie, have been treated with opioids for at least the 5 consecutive days prior to dosing and with at least 20 mg daily of oxycodone or the equivalent during at least the last 48 hours prior to the start of study drug dosing and have tolerated the therapy, as demonstrated at the start of study drug dosing by:
(a) A normal respiratory rate for age,
(b) Pulse oximetry (SpO2) ≥ 92% on room air, and
(c) No significant (grade 3 or 4) opioid-induced somnolence based on the University of Michigan Sedation Scale (UMSS) and the investigator’s judgment;
Patients who are currently using transdermal fentanyl should have been on the patch for at least 3 days before removing the patch and oxycodone HCl CR treatment can only be initiated at least 18 hours following the removal of the
transdermal fentanyl patch.
3) Patients must not require more than a 240 mg total daily dose of oxycodone HCl CR tablets;
4) Patients must be willing and able to swallow the oxycodone HCl CR tablets whole;
5) Patients must be able to understand and complete the age appropriate scale to rate pain intensity, ie, patients must not have a cognitive developmental delay or any other condition that would preclude them from completing age appropriate pain scale;
6) Patients must have a parent/caregiver who can perform study assessments, including the assessment of UMSS, Functional Disability Inventory (FDI), and Parent/Caregiver-Assessed Global Impression of Change (PGIC); and record the assessment scores, each dose of oxycodone HCl CR tablets, and each dose of supplemental pain medication;
7) Female patients of childbearing age must have a negative pregnancy test within 24 hours prior to study drug administration and be nonlactating;
8) Female patients who are sexually active must be using an acceptable method of birth control;
9) Patients and parents/caregivers who are willing and able to be compliant with the protocol, are capable of patient evaluation, are able to read and understand questionnaires, are willing and able to use a diary, and are able to read, understand, and sign the written informed consent and/or assent.
|
|
| E.4 | Principal exclusion criteria |
1) Female patients who are pregnant or lactating;
2) Patients who are allergic to oxycodone or have a history of allergies to other opioids (this criterion does not include patients who have experienced common opioid side effects [eg, nausea, constipation]);
3) Patients who have had surgery within 120 hours prior to Day 1 (day of first dose of study drug);
4) Patients who have received epidural opioids < 2 hours prior to the first dose of study drug or who have
received epidural morphine < 12 hours prior to the first dose of study drug;
5) Patients taking moderate to strong CYP3A4 inhibitors if the dose has not been stable for at least 1 month;
6) Patients taking moderate to strong CYP3A4 inhibitors if the dose has been stable for at least 1 month but the adjusted starting dose determined for oxycodone HCl CR is less than 20mg daily;
7) Patients for whom it is anticipated that therapy with a moderate to strong CYP3A4 inhibitor will be initiated during the study, after the screening visit;
8) Patients who are cyanotic postoperatively;
9) Patients who have a history of sleep apnea within the past year;
10) Patients who have a history of cystic fibrosis;
11) Patients who have a current history of malabsorption syndrome;
12) Patients who have a current history of paralytic ileus;
13) Patients who require mechanical ventilation;
14) Patients who are contraindicated for the use of opioids;
15) Patients who are contraindicated for blood sampling;
16) Patients who are currently being maintained on methadone for pain;
17) Patients who have a life expectancy of less than 2 weeks;
18) Patients who have an abnormality on vital signs, physical examination, or laboratory testing significant enough that the investigator deems the patient is not appropriate for the study;
19) Patients with hepatic impairment as evidenced by serum alanine amino transferase (ALT) or serum aspartate amino transferase (AST) > 5 times the upper limit of normal (ULN) for age;
20) Patients with evidence of impaired renal function (serum creatinine > 2 times the upper limit of normal [ULN] for age);
21) Patients who have any planned surgery during the course of the study, with the exception of the placement of central or peripheral venous access devices;
22) Patients who, in the opinion of the investigator, are unsuitable to participate in this study for any other reason.
23) Patients currently taking an investigational medication/therapy at the start of screening or during the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Analysis:
Safety variables will be summarized descriptively within age group for the safety population.
Safety assessments to be summarized include reports of adverse events, clinical laboratory test results, vital signs measurements, pulse oximetry (SpO2), and somnolence assessments. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AE assessed throughout the study. Vital signs, weight (predose and visit 3), height (predose) and pulse oximetry before first dose of ORF tablets and every 30 minutes for 90 minutes after first dose for all patients, after first increased dose of any uptitration for inpatients and patients receiving first increased dose. Medical staffs assess inpatients, for vital signs and pulse oximetry at 3 and 4 hours postdose, every 4 hours for 48 hours after first dose and after first increased dose of uptitration. UMSS
assessed before dose 1, postdose 1 on day 1, and at first increased dose for each uptitration. If patient is asleep, UMSS assessed when patient
awakens. For each uptitration, UMSS assessed approximately 24 and 48 hours after first increased dose. Lab tests at screening and wk 4. |
|
| E.5.2 | Secondary end point(s) |
Efficacy Analysis:
All efficacy variables (FPS-R, 100-mm VAS, FDI, PGIC and supplemental opioid analgesic use) will be listed for patients in the safety population.
Data will be summarized by age group (6 to < 12 years and ≥ 12 to ≤ 16 years) and by time point as appropriate. Summaries will include
descriptive statistics along with the associated 95% confidence intervals if deemed appropriate.
Pharmacokinetic Analysis:
All concentration data will be listed for patients in the FAP for PK. PK results will be included and presented in a separate population PK report. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: a)Patients (6 to <12 yrs) assess Pain right now on FPS-R and parents/caregivers record in Diary before first dose and 90 minutes
postdose on day 1 and, thereafter, during AM and PM approximately at time of each dosing of ORF tablet. Patients (≥12 to ≤16 yrs) assess
Pain right now on 100-mm VAS before first dose and 90 minutes postdose on day 1 and, thereafter, during AM and PM at time of each
dosing of ORF tablet. b) FDI: screening, wk 2 and 4. c) PGIC: wk 4. PK samples collected after first dose on day 1 (one sample 2-4 hours after
the dose and one sample 4-6 hours after dose with approximately 2 hours between samples) and immediately pre-dose (morning or evening
dose) and 2-4 hours after that dose at visit 2 and/or visit 3, total of 4-6 samples collected for all patients. |
|
| 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 | No |
| 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) | No |
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| For only outpatients, Oxycodone HCl CR tablets will be administered as directed by IVRS/IWRS. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Open-label, no comparator |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Croatia |
| Estonia |
| Finland |
| Germany |
| Greece |
| Guatemala |
| Hungary |
| India |
| Israel |
| New Zealand |
| Panama |
| Poland |
| Romania |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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