Safety, Pharmacokinetics (PK), and Efficacy of Buprenorphine Transdermal System (BTDS) in Children

Study Overview
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Brief Summary
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The purpose of this study is to characterize the safety, PK, and efficacy of BTDS in patients of ages 7 to 16 years.

Detailed Description
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A study of safety, PK, and efficacy of BTDS in patients of ages 7 to 16 years, inclusive, who require continuous opioid analgesia for moderate to severe pain.

Official Title
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An Open-label, Multicenter Study of the Safety, Pharmacokinetics, and Efficacy of Buprenorphine Transdermal System (BTDS) in Children From 7 to 16 Years of Age, Inclusive, Who Require Continuous Opioid Analgesia for Moderate to Severe Pain

Conditions
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Pain

Intervention / Treatment
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* Drug: Buprenorphine transdermal system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria include: Male and female patients, 7 to 16 years of age, inclusive, with malignant and/or nonmalignant moderate to severe pain requiring or anticipated to require continuous, around-the-clock, opioid treatment for at least 2 weeks (based on the investigator's judgment); Patients must have written informed consent provided by the parent or legal guardian and assent provided by the patient, when appropriate; Patients on incoming opioids must be taking ≤ 80 mg/day morphine or equivalent if aged 12 to 16 years or ≤ 40 mg/day morphine or equivalent if aged 7 to 11 years prior to the screening visit; Patients and patient's parent/caregiver must be compliant with the protocol, ie, must be able to perform study assessments and understand and complete the age-appropriate scale to rate pain intensity. Patients must not have a cognitive developmental delay or any other condition that would preclude them from completing the age-appropriate pain scale. Exclusion Criteria include: Patients who are allergic to buprenorphine or have a history of allergies to other opioids (this criterion does not include patients who have experienced common opioid side effects [eg, nausea, constipation]) or who have allergies or other contraindications to transdermal delivery systems or patch adhesives; Patients with a dermatological disorder, including burn and skin graft sites, at any relevant patch application site that would preclude proper placement and/or rotation of BTDS patches; Patients with evidence of impaired renal function; Patients with hepatic impairment; Patients with history of seizures; Patients with intracranial pressure; Patients who have a history of sleep apnea within the past year; Patients who require mechanical ventilation during study treatment period, are cyanotic, or who have unstable respiratory disease; Patients with clinically significant structural heart disease or a pacemaker; Patients with clinically unstable cardiac disease; Patients who receive or anticipate to receive investigational medication/therapy during study drug treatment period. Other protocol-specific inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 16 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Overall BTDS<br>Buprenorphine transdermal system | Drug: Buprenorphine transdermal system<br>* Buprenorphine transdermal system 2.5 mcg/h, 5 mcg/h, 10 mcg/h or 20 mcg/h applied transdermally for 7-day wear.<br>* Other names: Butrans;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Adverse Events as a Measure of Safety | Safety assessments consisted of reports of AEs, vital signs (blood pressure, pulse rate, respiratory rate, and temperature), weight, hemoglobin-oxygen saturation measured by pulse oximetry (SpO2), clinical laboratory tests, somnolence (assessed by the University of Michigan Sedation Scale [UMSS]), conventional 12-lead electrocardiograms (ECGs), and 24-hour digital 12-lead ECGs (Holter monitor). Safety variables were summarized descriptively within age group for the safety population. | Up to 28 weeks | 
| Pharmacokinetics (PK) of Buprenorphine Following Transdermal Administration: Apparent Clearance (CL/F) | The population PK (PopPK) of BTDS buprenorphine in pediatric patients ages 7 to 16 years was described by a 2-compartment model with sequential zero- and first-order absorption from the patch. A fixed allometric relationship was used to describe the effects of changes in ideal body weight (IBW) across pediatric patients on all clearance and volume parameters. Given the sparse sample collections, small sample size, and complexity of the absorption process with the patch formulation, this PopPK model was fit to the pediatric data using nonlinear mixed effects modeling (NONMEM) Bayes method with selective use of priors from previous adult PopPK results. Estimates of fixed effects from the final model were used to calculate the CL/F after patch dosing given the covariate distribution in the PopPK dataset and the typical weights from children in the National Health and Nutrition Examination Survey (NHANES) dataset. | Day 1, end of week 1, days 9/10, end of week 2, and end of week 4 or at discontinuation prior to end of study visit | 
| Pharmacokinetics (PK) of Buprenorphine Following Transdermal Administration: Apparent Volume of Distribution (Vc/F) | The population PK (PopPK) of BTDS buprenorphine in pediatric patients ages 7 to 16 years was described by a 2-compartment model with sequential zero- and first-order absorption from the patch. A fixed allometric relationship was used to describe the effects of changes in ideal body weight (IBW) across pediatric patients on all clearance and volume parameters. Given the sparse sample collections, small sample size, and complexity of the absorption process with the patch formulation, this PopPK model was fit to the pediatric data using nonlinear mixed effects modeling (NONMEM) Bayes method with selective use of priors from previous adult PopPK results. Estimates of fixed effects from the final model were used to calculate the Vc/F after patch dosing given the covariate distribution in the PopPK dataset and the typical weights from children in the National Health and Nutrition Examination Survey (NHANES) dataset. | Day 1, end of week 1, days 9/10, end of week 2, and end of week 4 or at discontinuation prior to end of study visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Right Now Assessment by Patients Aged 7 to 11 Years, Inclusive | Pain right now was assessed using the Faces of Pain Scale-Revised (FPS-R). The FPS-R is a horizontal row of 6 faces representing pain intensity, with no hurt at the far left and hurts worst at the far right; the intensities are scored as 0, 2, 4, 6, 8, or 10. A score of 0=no pain, and 10=very much pain. For screening to week 4, pain right now was assessed at 30 minutes before initial BTDS application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline score was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. The study measured pain right now for weeks 6-24 once a week at approximately 8 PM while on treatment; however, no patients in this age group were treated beyond week 12. | Up to 24 weeks | 
| Pain Right Now Assessment by Patients Aged 12 to 16 Years, Inclusive | Pain right now was assessed using a 100-mm visual analogue scale (VAS). The 100-mm VAS is a 100-mm line with 1 end marked as no pain and the other marked as pain as bad as it could be. The patient was asked to make a mark on that line indicating his or her level of pain. Pain right now score was defined as the distance (in mm) from the no pain end to the patient's mark; 0=no pain and bigger numbers indicate more pain. For screening to week 4, pain right now was assessed 30 minutes before initial BTDS application on day 1; one hour after initial BTDS application on day 1; thereafter, once daily at approximately 8 PM for the first 4 weeks. Baseline was the last assessment prior to the first dose. For weeks 1-4, weekly averages of the pain right now scores were calculated using the sum of all available pain right now scores recorded daily during a given week divided by the number of available scores. For weeks 6-24, pain right now was measured once a week at approximately 8 PM. | Up to 24 weeks | 
| Parent/Caregiver-assessed Global Impression of Change (PGIC) | The PGIC rating score variable was collected on a 7-point scale ranging from 1 to 7 (where 1 = very much improved; and 7 = very much worse). The PGIC is designed to assess overall satisfaction with the treatment. The PGIC score was summarized using the number and percent of patients in each of the 7 possible response categories overall and by age group. PGIC was assessed by the parent/caregiver at the end of treatment visit or early discontinuation visit. | End of treatment (week 24) or early discontinuation visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, Opioid, Analgesia, Moderate to severe pain