E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Opioid induced constipation |
|
E.1.1.1 | Medical condition in easily understood language |
Constipation resulting from treatment with a class of drugs called opioids |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
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 | 10071128 |
E.1.2 | Term | Opioid induced constipation |
E.1.2 | System Organ Class | 100000004856 |
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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 |
To evaluate the pharmacokinetics, safety and tolerability of naldemedine in paediatric patients who are receiving or who are about to receive treatment with opioids |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of naldemedine after a single oral dose of
naldemedine.
To evaluate the PK of naldemedine after multiple, once daily oral doses of naldemedine through population PK in paediatric patients.
To evaluate the safety and tolerability of naldemedine after multiple, once daily oral doses of naldemedine in paediatric patients.
To evaluate the palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients ≥ 6 months of age and < 18 years of age
2. Patients receiving treatment or expected to receive treatment with an opioid for pain
3. Have either newly diagnosed constipation, a history of constipation treated with laxatives, or expected to develop constipation after opioid treatment.
4. Patients able to remain in the clinic for blood sampling for at least 12 hours following the first study intervention dose and able to return for blood sampling at the 24-hour timepoint.
5. Patients able to comply with meal, tobacco, and concomitant medication restrictions
6. BMI within approximately the 3rd to 97th percentile for their age according to the World Health Organization (WHO) Child Growth Standard
7 a. Prepubescent male patients may participate. A postpubescent and sexually active male patient must agree to use appropriate contraception during the study and refrain from donating sperm during this period.
7 b. A premenarchal female patient is eligible to participate. If a female patient is menarchal she must be not pregnant, not breastfeeding, and agree to follow appropriate contraceptive guidance during the treatment period and for at least 30 days after the last dose of naldemedine. |
|
E.4 | Principal exclusion criteria |
1. Patients with a history of a GI neoplasm or an ongoing GI-related issue or any
recent (within last 1 year) or planned GI tract surgery
2. Patients with signs or symptoms of GI obstruction
3. Patients who have a nasogastric tube.
4. Patients who have reported no bowel movements for 7 consecutive days at the
time of obtaining informed consent or on the initial day of study intervention
administration (Study Day 1)
5. Patients with a history of more than 1 week of CTCAE Grade 3 neutropenia or
thrombocytopenia with clinical sequelae
6. Patients who need mechanical ventilation
7. Patients who have severe CTCAE Grade 3 or above hepatic or renal impairment
including end-stage renal disease requiring hemodialysis
8. Patients who have a history of hypersensitivity to naldemedine or any of its ingredients.
9. Patients who have previously received naldemedine.
10. Patients currently receiving their first cycle of chemotherapy
11. Patients currently participating in another study of an investigational drug product or have received another investigational drug product within 30 days or 5 half-lives, whichever is longer, before baseline
12. Positive pregnancy test for female patients of childbearing potential |
|
E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the pharmacokinetics (PK) of naldemedine and nor-naldemedine after a single oral dose of naldemedine
-- PK parameters using standard non-compartmental method, e.g. Cmax, Tmax, AUC, AUC0-last, AUC0-inf, λz, t1/2,z of naldemedine and nor-naldemedine; and CL/F, MRT, and Vz/F for naldemedine only, and metabolic ratio of Cmax of nor-naldemedine to Cmax of naldemedine [MRM/U, Cmax] andmetabolic ratio of AUC of nor-naldemedine to AUC of naldemedine [MRM/U, AUC] for nor-naldemedine only |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
To evaluate the safety and tolerability of naldemedine after a single oral dose of naldemedine
-- Using results of physical examinations, vital signs, 12-lead ECGs, clinical laboratory tests, treatment-emergent adverse events (TEAEs), treatment-related TEAEs,including gastrointestinal (GI) events, and
serious adverse events (SAEs) on Study Day 1
To evaluate the PK of naldemedine after multiple, once daily oral doses of naldemedine through population PK
-- using Results of population PK analysis
PK parameters using population PK analysis (e.g. Cmax, Tmax, AUC0-τ, accumulation ratio for Cmax calculated as ratio of Day 7 to Day 1 Cmax (RCmax), and accumulation ratio for AUC calculated as ratio of Day 7 to Day 1 AUC (RAUC) for naldemedine only
To evaluate the safety and tolerability of naldemedine after multiple, once daily oral doses of naldemedine
-- using results of physical examinations, vital signs, 12-lead ECGs, clinical laboratory tests, TEAEs, treatment-related TEAEs including GI events, SAEs, and pain assessment(s) on Study Days 2 through 7
To evaluate the palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets
--using results of self-reported visual analog scale (VAS) for palatability assessments of naldemedine powder for oral suspension for patients ≥ 6 years of age
-- Results of investigator’s or patient’s parent/legal guardian assessment of palatability of naldemedine powder for oral suspension for patients < 6 years of age, and, if possible, patients’ self-assessment using a VAS with facial hedonic scale
-- Results of self-reported ease of swallowing of naldemedine tablets
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Results of physical examinations (including assessment of opioid
withdrawal symptoms), vital signs (blood pressure, pulse rate,
respiratory rate, and body temperature), 12 lead electrocardiograms
(ECGs), clinical laboratory tests, treatment-emergent adverse events
(TEAEs), treatment-related TEAEs, including GI events, and serious
adverse events (SAEs) on Study Day 1
●Results of population PK analysis
●PK parameters using population PK analysis (eg, Cmax, Tmax, AUC0-τ,
accumulation ratio for Cmax calculated as ratio of Day 7 to Day 1 Cmax
(RCmax), and accumulation ratio for AUC calculated as ratio of Day 7 to
Day 1 AUC (RAUC) for naldemedine only |
|
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 | No |
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) | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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 | No |
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 | No |
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
| 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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
France |
Germany |
Hungary |
Italy |
Netherlands |
Serbia |
Spain |
|
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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |