Safety and Pharmacokinetic Study of EMBEDA in Children Ages 7-17 With Pain

Study Overview
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Brief Summary
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Safety and pharmacokinetics of an abuse-deterrent, extended-release formulation of morphine sulfate with a sequestered naltrexone core in children 7-17 with moderate-severe pain.

Detailed Description
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Subjects, once stabilized to Embeda, need only complete a minimum of 2 of the 6 week study duration to satisfy the PK endpoint. A safety follow-up visit is required at 1 week post-last dose.

Official Title
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AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND PHARMACOKINETICS OF PF-06412528 IN CHILDREN 7-17 YEARS FOR THE TREATMENT OF MODERATE-TO-SEVERE PAIN

Conditions
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Moderate-severe Pain

Intervention / Treatment
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* Drug: Ages 7-11
* Drug: ages 12-17


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children 7-17 with moderate to severe pain requiring around the clock treatment with an opioid analgesic. Be an experienced opioid user, defined as any subject treated with opioid therapy, equivalent or equal to >20 mg per day of morphine, for a period of 3 consecutive days immediately prior to first day of dosing. Exclusion Criteria: Columbia-Suicide Severity Rating Scale (C-SSRS) for suicidal ideation and behavior in past year. Hypersensitivity to morphine, naltrexone. A life expectancy (assessed by investigator) of less than 6 months or is no longer capable of taking medication orally. Undergone surgery within 3 days prior to the first day of dosing.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 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: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Embeda<br>One arm, open label, active | Drug: Ages 7-11<br>* Oral/Capsule, once per day or twice per day dosing; Treatment duration consists of a 1 to 4 week Conversion/Titration Phase leading to a 2 to 6 week Maintenance Treatment duration.<br>Drug: ages 12-17<br>* Oral/Capsule, once per day or twice per day dosing; Treatment duration consists of a 1 to 4 week Conversion/Titration Phase leading to a 2 to 6 week Maintenance Treatment duration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 1 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Week 1 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 2 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Week 2 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 3 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Week 3 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 4 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Week 4 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Early Termination Before Week 4 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Early Termination before Week 4 (anytime between Week 1 to Week 4) | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Screening on Week 5 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Screening before treatment started at Week 5 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Day 1 of Week 5 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Day 1 of Week 5 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 6 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Week 6 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 8 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Week 8 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 10 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Week 10 | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Early Termination Before Week 10 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Early Termination before Week 10 (anytime between Week 5 to Week 10) | 
| Apparent Oral Clearance (CL/F) of PF-06412528 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. | Anytime post-dose on Visit 4 (Week 4) | 
| Average Concentration at Steady-state (Css, av) of PF-06412528 | Css, av was defines as the average steady state concentration of a drug (steady state has been achieved when the rate of drug administration and the rate of drug elimination are equal). | Anytime post-dose on Visit 4 (Week 4) | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Screening Before Day 1 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | At Screening (2 weeks before Day 1 of study) | 
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Day 1 | COWS is a clinician-administered instrument, to assess participants' clinical opiate withdrawal level. The scale ranges from 0 (none symptoms) to 48 (severe symptoms), higher score = more severe withdrawal. Scores category: 0 to 4 = none to minimal, 5 to 12 = mild, 13 to 24 = moderate, 25 to 36 = moderately severe withdrawal and 37 to 48 = severe withdrawal. Participants experiencing a COWS score greater than equal to (>=) 13 is treated for opiate withdrawal signs and symptoms according to the investigator's medical judgment. In this outcome measure, participants as per COWS score categories are reported. Only those COWS categories are presented which had at least 1 participant for any reporting arm. | Day 1 (Pre-dose) | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Week 1 to Week 4 | An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious adverse events. | Week 1 to Week 4 | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Week 5 to Week 10 | An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious adverse events. | Week 5 to Week 10 | 
| Number of Participants With Treatment Emergent Adverse Events According to Severity: Week 1 to Week 4 | An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity; mild (does not interfere with participant's usual function), moderate (interferes to some extent with participant's usual function) and severe (interferes significantly with participant's usual function).A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious adverse events. | Week 1 to Week 4 | 
| Number of Participants With Treatment Emergent Adverse Events According to Severity: Week 5 to Week 10 | An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity; mild (does not interfere with participant's usual function), moderate (interferes to some extent with participant's usual function) and severe (interferes significantly with participant's usual function). A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious adverse events. | Week 5 to Week 10 | 
| Number of Participants With Treatment Emergent Treatment Related Adverse Events: Week 1 to Week 4 | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. Relatedness to PF-06412528 was assessed by the investigator. | Week 1 to Week 4 | 
| Number of Participants With Treatment Emergent Treatment Related Adverse Events: Week 5 to Week 10 | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. Relatedness to PF-06412528 was assessed by the investigator. | Week 5 to Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pre-defined Criteria of Vital Signs | Pre-defined criteria of vital signs included supine diastolic blood pressure (DBP) change from baseline greater than or equal to (>=) 20 millimeter of mercury (mmHg): increase and decrease; supine systolic blood pressure (SBP) change from baseline >=30 mmHg: increase and decrease. | Week 1 up to Week 10 | 
| Number of Participants With Laboratory Test Abnormalities | Laboratory parameters included: hematology (hemoglobin: <0.8*LLN, hematocrit: <0.8*LLN, red blood cell: <0.8* LLN, platelet <0.5*LLN; >1.75*ULN and white blood cell count <0.6*LLN, neutrophils <0.8* LLN, eosinophils >1.2*ULN, monocytes >1.2*ULN, basophils >1.2*ULN and lymphocytes <0.8* LLN), chemistry (blood urea nitrogen >1.3*ULN, creatinine>1.3*ULN, sodium <0.95*LLN, potassium <0.9*LLN, >1.1*ULN, aspartate aminotransferase >3.0*ULN, alanine aminotransferase >3.0*ULN, total bilirubin >1.5*ULN, alkaline phosphatase >3.0*ULN, albumin <0.8*LLN, total protein<0.8*LLN, >1.2*ULN, Albumin <0.8*LLN, Blood Urea Nitrogen >1.3*ULN, Creatinine >1.3*ULN, HDL Cholesterol <0.8*LLN, Chloride <0.9*LLN, Phosphate <0.8*LLN, Bicarbonate <0.9*LLN, Glucose <0.6*LLN, Creatine Kinase >2.0*ULN, Urobilinogen >=1) and urinalysis (specific gravity <1.003, pH <4.5 urine glucose >=1, ketones >=1 urine protein >=1, urine bilirubin >=1, nitrite >=1, urine leukocytes >=20). | Week 1 up to Week 10 | 
| Apparent Volume of Distribution (Vz/F) of PF-06412528 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | Anytime post-dose on Visit 4 (Week 4) | 
| Dose-Exposure Relationship of Metabolites of Morphine, Naltrexone and 6-β-Naltrexol |  | Anytime post-dose on Visit 4 (Week 4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, pain indication, controlled release morphine