E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Opioid induced constipation |
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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 | 24.0 |
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 |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of naldemedine after a single oral dose of naldemedine in paediatric patients who are receiving or who are about to receive opioids. To evaluate the PK of naldemedine after multiple, once daily oral doses of naldemedine through population PK in paediatric patients who are receiving or who are about to receive opioids. To evaluate the palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients ≥ 2 years of age and < 18 years of age at the time of the signing of the informed consent form. 2. Patients with cancer or non-cancer pain who are receiving (or who are about to receive) acute or chronic treatment with opioids 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 time point. 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. Male Patients: Based on the Clinical Trials Facilitation and Coordination Group (CTFG) guidance, no contraception measures are required for male patients because naldemedine is not genotoxic and is categorized ‘unlikely’ for the risk of human teratogenicity/foetotoxicity. 7 b. Female patients: A female patient is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: - Is a woman of nonchildbearing potential (WONCBP) OR - Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method as described in protocol, during the treatment period and for 30 days following the last dose of study drug . The investigator should evaluate the potential for contraceptive method failure (eg. noncompliance, recently initiated) in relationship to the first dose of study drug. - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) at screening and within 24 hours of the first dose of naldemedine. - If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the patient must be excluded from participation if the serum pregnancy result is positive. - Additional requirements for pregnancy testing during and after study intervention as per protocol. 8. Each patient’s parent/legal guardian must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. |
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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 or patients with recurrent obstruction who may be at increased risk of GI perforation. 3. Patients who are unable to eat/swallow or have need of 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 haemodialysis, as determined by the investigator 8. Patients that have any progressive neurological disorders or potential disruption to the blood-brain barrier (e.g., primary brain malignancies, CNS metastases, active multiple sclerosis, etc.) considering the risk of opioid withdrawal or reduced analgesia. 9. Patients who have a history of hypersensitivity to naldemedine or any of its ingredients. 10. Patients who have previously received naldemedine. 11. Patients currently receiving their first cycle of chemotherapy 12. 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 13. Positive pregnancy test for female patients of childbearing potential |
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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 |
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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 (including assessment of opioid withdrawal symptoms and pain intensity), vital signs, 12-lead ECGs, safety laboratory tests, treatment-emergent adverse events (TEAEs), treatment-related TEAEs,including gastrointestinal (GI) events, and serious adverse events (SAEs) on Study Days 1 through 7 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 palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets --using results of self-reported visual analogue 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 ≥ 2 years to < 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
To evaluate the safety and tolerability of naldemedine after a single oral dose of naldemedine: Days 1 through 7 To evaluate the PK of naldemedine after multiple, once daily oral doses of naldemedine through population PK: ratio of Day 7 to Day 1 To evaluate the palatability of naldemedine powder for oral suspension and the ability to swallow naldemedine tablets: during the study
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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 | Yes |
E.7.1.3.1 | Other trial type description |
This is a Phase 1/2 study but not within E.7.1.1 or E7.1.2 groups |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Netherlands |
Spain |
Italy |
Belgium |
Serbia |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |