Safety and Pharmacokinetics Study of Naldemedine in Paediatric Participants Receiving Opioids

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the pharmacokinetic (PK) profile of naldemedine and nor-naldemedine after a single oral dose of naldemedine in pediatric participants who are receiving or about to receive opioids.

Official Title
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A Phase 1/2, Multicentre, Open-label Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Naldemedine in Paediatric Patients Who Are Receiving or Who Are About to Receive Treatment With Opioids

Conditions
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Opioid-Induced Constipation (OIC)

Intervention / Treatment
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* Drug: Naldemedine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Characteristics Participants with cancer or non-cancer pain who are receiving (or who are about to receive) acute or chronic treatment with opioids. Participants with either newly diagnosed constipation, a history of constipation treated with laxatives, or are expected to develop constipation after opioid treatment. Able to remain in the clinic for blood sampling for at least 12 hours following the first study intervention dose and are able to return for blood sampling at the 24-hour time point. Weight Body mass index within approximately the 3rd to 97th percentile for their age according to the World Health Organization Child Growth Standards. Exclusion Criteria: Medical Conditions History of a gastrointestinal (GI) neoplasm or an ongoing GI-related issue or any recent (within last 1 year) or planned GI tract surgery. Signs or symptoms of GI obstruction or participants with recurrent obstruction who may be at increased risk of GI perforation. Inability to eat/swallow or have need of a nasogastric tube. No bowel movements reported for 7 consecutive days at the time of obtaining informed consent or on the initial day of study intervention administration (Study Day 1). History of more than 1 week of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 neutropenia or thrombocytopenia with clinical sequelae. Participants who need mechanical ventilation. Severe CTCAE Grade 3 or above hepatic or renal impairment including end-stage renal disease requiring hemodialysis, as determined by the investigator. Progressive neurological disorders or potential disruption to the blood-brain barrier (for example, primary brain malignancies, central nervous system metastases, active multiple sclerosis, etc.) considering the risk of opioid withdrawal or reduced analgesia. Prior/Ongoing Medications Currently receiving the first cycle of chemotherapy. Previously received naldemedine. Other Exclusions - Positive pregnancy test for females of childbearing potential. Note: Other protocol-defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: ≥ 12 to < 18 Years<br>Participants will receive 0.05 milligrams (mg) to 0.2 mg naldemedine based on their body weight once daily for 7 days. | Drug: Naldemedine<br>* Administered as an oral tablet (0.2 mg dose level only), or oral suspension (all dose levels)<br>* Other names: Rizmoic;|
| Experimental: Cohort 2: ≥ 6 to < 12 Years<br>Participants will receive 0.05 mg to 0.2 mg naldemedine based on their body weight once daily for 7 days. | Drug: Naldemedine<br>* Administered as an oral tablet (0.2 mg dose level only), or oral suspension (all dose levels)<br>* Other names: Rizmoic;|
| Experimental: Cohort 3: ≥ 2 to < 6 Years<br>Participants will be enrolled in this cohort after the safety and PK data has been evaluated for cohorts 1 and 2. Participants will receive 0.05 mg to 0.2 mg naldemedine based on their body weight once daily for 7 days. | Drug: Naldemedine<br>* Administered as an oral tablet (0.2 mg dose level only), or oral suspension (all dose levels)<br>* Other names: Rizmoic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Naldemedine and Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Time to Achieve Maximum Plasma Concentration (Tmax) of Naldemedine and Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of Naldemedine and Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| AUC Extrapolated From Time Zero to Infinity (AUC0-inf) of Naldemedine and Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Terminal Elimination Rate Constant (λz) of Naldemedine and Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Terminal Elimination Half-life (t1/2,z) of Naldemedine and Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Apparent Total Clearance (CL/F) of Naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Mean Residence Time (MRT) of Naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Apparent Volume of Distribution in the Terminal Phase (Vz/F) of Naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Metabolic Ratio of Cmax of Nor-naldemedine to Cmax of Naldemedine (MRM/U, Cmax) for Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 
| Metabolic Ratio of AUC of Nor-naldemedine to AUC of Naldemedine (MRM/U, AUC) for Nor-naldemedine |  | Day 1: 0.5, 1, 5, and 12 hours postdose; Day 2: 24 hours post Day 1 dose, before administering the Day 2 dose; Day 7 (Cohort 1 only): Predose and 1 hour postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Treatment-emergent Adverse Events |  | Day 1 through Day 7 | 
| Population PK Analysis: Cmax of Naldemedine |  | Day 1 through Day 7 | 
| Population PK Analysis: Tmax of Naldemedine |  | Day 1 through Day 7 | 
| Population PK Analysis: AUC From Time Zero to tau (AUC0-tau) of Naldemedine |  | Day 1 through Day 7 | 
| Population PK Analysis: Accumulation Ratio for Cmax Calculated as Ratio of Day 7 to Day 1 Cmax (RCmax) of Naldemedine |  | Day 1 through Day 7 | 
| Population PK Analysis: Accumulation Ratio for AUC Calculated as Ratio of Day 7 to Day 1 AUC (RAUC) of Naldemedine |  | Day 1 through Day 7 | 
| Palatability of Naldemedine Powder for Oral Suspension in Participants Aged 6 Years and Above | Palatability will be assessed by participant self-reporting using a visual analogue scale (VAS). | Day 1 through Day 7 | 
| Palatability of Naldemedine Powder for Oral Suspension in Participants Aged 2 to Less Than 6 Years | Palatability will be assessed by the investigator or a participant's parent/legal guardian and, if possible, by participant self-reporting using a VAS with facial hedonic scale. | Day 1 through Day 7 | 
| Ability to Swallow Naldemedine Tablets | Ability to swallow will be assessed by self-reported ease of swallowing after the first dose. Willingness to swallow will be assessed based on the participant's behavior indicative of a negative response and the response to the taste of naldemedine powder for oral suspension formulation compared to the participant's response to all other oral medications currently being given. | Day 1 through Day 7 |