| 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 |
| Treatment of constipation after taking opioid drugs |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
| 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 |
|
| 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 characterize the pharmacokinetics (PK) of naloxegol after single oral dose and through population PK in paediatric patients with opioid induced constipation (OIC). |
|
| E.2.2 | Secondary objectives of the trial |
· To characterize the PK of naloxegol after multiple, once-daily, oral dosing in paediatric OIC patients who continue participation beyond Day 1. A minimum of 3 days of dosing is required for multiple-dose PK analysis.
· To evaluate the acceptability of the study medication in paediatric OIC patients through assessment of: 1) palatability of liquid formulation and, 2) the ability of the patient to swallow the tablet.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patients between the ages of ≥ 6 months and < 18 years.
- Patients with malignant or non-malignant pain who are receiving (or are about to receive) acute or chronic treatment with opioids.
- In the investigator’s judgment, patients must be either newly diagnosed with constipation or patients must have a history of constipation treated with laxatives or are expected to develop constipation after initiation of opioid treatment.
- Female patients of childbearing potential must have a negative urine pregnancy test at screening. Females of childbearing potential must either not be sexually active or be using an adequate birth control method throughout the duration of the study.
|
|
| E.4 | Principal exclusion criteria |
1. Involvement of a parent or guardian in the planning and/or conduct of the study (applies to both KKI staff and/or staff at the study site).
2. Previous enrolment in the present study with intake of naloxegol investigational product.
3. Current acute or chronic use of methadone.
4. For patients 6-12 months old, history of major corrective or reconstructive gastrointestinal surgery (except pyloric stenosis) in the last 6 months or possible need for corrective or reconstructive gastrointestinal surgery in the next month, or history of post-surgical ileus. For patients over 1 year of age, history of previous gastrointestinal surgery in the last 6 months (does not include placement of enteral tubes or liver biopsies).
5. History of an intra-abdominal or peritoneal neoplasm or an ongoing GI-related issue (e.g., inflammatory bowel disease, connective tissue disorders like Ehler Danlos, dermatomyositis, scleroderma) which, in the opinion of the investigator, may be contributing to constipation as a result of mechanical obstruction or may place the patient at increased risk for intestinal perforation by impairing the local or global structural integrity of the GI tract.
6. Signs or symptoms of GI obstruction including faecal impaction requiring medical intervention. History of GI obstructive conditions (e.g. Hirschsprung’s disease, malrotation, volvulus, pseudo-obstruction syndromes).
7. Currently active medical conditions or ongoing treatments (e.g. irinotecan) that may result in diarrhoea or intermittent loose stools during the screening or treatment period.
8. Significant cardiorespiratory dysfunction or haemodynamic instability.
9. Evidence of known widespread cancer metastases in the CNS.
10. Radiotherapy between the diaphragm and the pelvis in the 4 weeks prior to screening or planned to be initiated during the treatment period.
11.Any of the following findings and/or conditions:
(a) For patients 6 -12 months old, any elevation of serum direct or indirect bilirubin and LFTs that have not undergone a medical work up. For patients over 1 year old, serum ALT or AST >2.5 x upper limit of normal (ULN) and/or serum bilirubin >1.2 x ULN (unless known to be due to Gilbert’s syndrome or sickle-cell disease).
(b)Creatinine clearance less than 60 ml/min/1.73 m2 (using the Shwartz formula*).
(c) Absolute neutrophil count (ANC) <1.0 x 10^9/L; haemoglobin <9 g/dL (or <7 g/dL
if known to be related to sickle cell disease) or, platelet count < 50,000/uL at the time of the first dose of naloxegol.
12. History (within past 3 months) of prolonged (> 10 days) neutropenia or thrombocytopenia with clinical sequelae.
13. Treatment with another experimental medication for which there is no current labelled therapy (adult or paediatric), currently or within the last 30 days.
14. Patients with cancer currently receiving the first cycle of chemotherapy, or due to receive a chemotherapeutic agent for the first time.
15. Life expectancy of < 3 months.
16. Treatment within 7 days of naloxegol dosing with any concomitant
medications known or expected to be significantly affected by naloxegol
administration or known to significantly affect naloxegol PK (See Section 7.7.2 for list of excluded concomitant medications)
17. Patients with clinically significant BBB disruptions (e.g., active multiple sclerosis, recent brain injury).
18. Patients with known hypersensitivity to other opioid antagonists
19. Patients with cancer-related pain who are at heightened risk of GI
perforation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Standard non-compartmental analysis approach: area under the plasma concentration-time curve from zero extrapolated to infinity (AUC), area under the plasma concentration-time curve from zero to the last quantifiable concentration (AUC(0-t)), maximum plasma concentration (Cmax), terminal half-life (t1/2λz), time to maximum plasma concentration (tmax), and mean residence time (MRT), oral clearance (CL/F) and apparent volume of distribution during the terminal phase (Vz/F).
Population pharmacokinetic modelling approach: population estimated structural PK parameters and influence of potential covariates |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 hour PK blood sampling after first dose and on day 7 |
|
| E.5.2 | Secondary end point(s) |
| Other additional multiple dose PK parameters, e.g., RAC(AUC) and Rac(Cmax). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24 hour PK blood sampling after first dose and on day 7 |
|
| 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 |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | 3 |
| 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 | 6 |
| 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 |
| Denmark |
| Israel |
| Netherlands |
| Norway |
| Spain |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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