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

• ClinicalTrials.gov Identifier: NCT02101554
• Recruitment Status: Terminated
• First Posted: April 2, 2014
• Results First Posted: July 10, 2020
• Last Update Posted: July 10, 2020
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: March 5, 2014
• First Posted Date: April 2, 2014
• Results First Submitted Date: June 23, 2020
• Results First Posted Date: July 10, 2020
• Last Update Posted Date: July 10, 2020
• Actual Study Start Date: April 24, 2015
• Actual Primary Completion Date: June 26, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 23, 2020)

• Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Week 1 to Week 4 [ Time Frame: 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.
• Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Week 5 to Week 10 [ Time Frame: 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.
• Number of Participants With Treatment Emergent Adverse Events According to Severity: Week 1 to Week 4 [ Time Frame: 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.
• Number of Participants With Treatment Emergent Adverse Events According to Severity: Week 5 to Week 10 [ Time Frame: 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.
• Number of Participants With Treatment Emergent Treatment Related Adverse Events: Week 1 to Week 4 [ Time Frame: 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.
• Number of Participants With Treatment Emergent Treatment Related Adverse Events: Week 5 to Week 10 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Screening Before Day 1 [ Time Frame: At Screening (2 weeks before Day 1 of study) ]
  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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Day 1 [ Time Frame: Day 1 (Pre-dose) ]
  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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 1 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 2 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 3 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 4 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Early Termination Before Week 4 [ Time Frame: Early Termination before Week 4 (anytime between Week 1 to 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Screening on Week 5 [ Time Frame: Screening before treatment started at 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Day 1 of Week 5 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 6 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 8 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Week 10 [ Time Frame: 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.
• Number of Participants With Clinical Opiate Withdrawal Scale (COWS) at Early Termination Before Week 10 [ Time Frame: Early Termination before Week 10 (anytime between Week 5 to 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.
• Apparent Oral Clearance (CL/F) of PF-06412528 [ Time Frame: Anytime post-dose on Visit 4 (Week 4) ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
• Average Concentration at Steady-state (Css, av) of PF-06412528 [ Time Frame: Anytime post-dose on Visit 4 (Week 4) ]
  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).

Original Primary Outcome Measures (submitted: March 28, 2014)

• Apparent Oral Clearance (CL/F) [ Time Frame: 4 weeks post-dose ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
• Volume of Distribution (Vd/F) [ Time Frame: 4 weeks post-dose ]
  Vd is the theoretical volume that the total amount of administered drug would have to occupy to provide the same concentration as it currently is in the blood plasma.

Current Secondary Outcome Measures (submitted: June 23, 2020)

• Number of Participants With Pre-defined Criteria of Vital Signs [ Time Frame: Week 1 up to Week 10 ]
  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.
• Number of Participants With Laboratory Test Abnormalities [ Time Frame: Week 1 up to Week 10 ]
  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).
• Apparent Volume of Distribution (Vz/F) of PF-06412528 [ Time Frame: Anytime post-dose on Visit 4 (Week 4) ]
  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.
• Dose-Exposure Relationship of Metabolites of Morphine, Naltrexone and 6-β-Naltrexol [ Time Frame: Anytime post-dose on Visit 4 (Week 4) ]

Original Secondary Outcome Measures (submitted: March 28, 2014)

Pharmacokinetic evaluation [ Time Frame: 4 weeks post-dose ]

Exposure levels of the metabolites of morphine and naltrexone in plasma samples

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Pharmacokinetic Study of EMBEDA in Children Ages 7-17 With Pain
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Moderate-severe Pain

Intervention

• Drug: Ages 7-11
  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.
• Drug: ages 12-17
  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.

Study Arms

Experimental: Embeda

One arm, open label, active

Interventions:

• Drug: Ages 7-11
• Drug: ages 12-17

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 30, 2019): 19
• Original Estimated Enrollment (submitted: March 28, 2014): 100
• Actual Study Completion Date: June 26, 2019
• Actual Primary Completion Date: June 26, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 7 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States
• Removed Location Countries: Puerto Rico

Administrative Information

• NCT Number: NCT02101554
• Other Study ID Numbers: B4541006; EMBEDA ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: June 2020