Study of BEMA™ Fentanyl in the Treatment of Breakthrough Pain in Cancer Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of BEMA Fentanyl (Onsolis) at any dose in the management of breakthrough pain in cancer subjects on background opioid therapy. The standard of care for these breakthrough pain episodes is a rapid onset, short acting analgesic with minimal associated sleepiness. Oral morphine, oxycodone and hydromorphone are routinely used, but because of slow and variable oral absorption, the pain control is not the best with these products. Oral transmucosal fentanyl citrate (OTFC) has been used successfully in treating breakthrough pain episodes associated with cancer. OTFC is a lozenge of fentanyl on a stick and is administered by continuously swabbing the interior of the subject's mouth until the product is dissolved (approximately 15 to 30 minutes). The buccal route of administration avoids the delay and variability associated with oral absorption.

Detailed Description
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This is a randomized, double-blind, placebo controlled, multiple cross-over study. Eligible subjects will be treated with open label BEMA fentanyl over a period of up to two weeks. Doses will be titrated upward, starting at 200 μg, until a dose is identified that produces satisfactory pain relief for at least 2 episodes. Those subjects who identify a dose of BEMA fentanyl that produces satisfactory relief of breakthrough pain episodes will enter the double-blind, placebo controlled period of the trial. They will receive 3 placebo doses and 6 BEMA fentanyl doses in a random sequence per randomization schedule.

Official Title
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A Double-blind, Placebo Controlled Evaluation of the Efficacy, Safety and Tolerability of BEMA™ Fentanyl in the Treatment of Breakthrough Pain in Cancer Subjects

Conditions
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Pain, Cancer

Intervention / Treatment
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* Drug: BEMA™
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant and non-lactating female. A female of child-bearing potential is eligible to participate in this study if she is using an acceptable method of birth control. 18 years or older Patient must have pain associated with cancer or cancer treatment. Patient must be on a stable current regimen of oral opioids equivalent to 60 - 1000 mg/day of oral morphine or 50 - 300 µg/hr of transdermal fentanyl (e.g. oxycodone 30 mg, methadone 20 mg, and hydromorphone 7.5 mg). Regularly experiences 1 - 4 breakthrough pain episodes per day that require additional opioids for pain control At least partial relief of breakthrough pain by use of opioid therapy Subject must be able to self-administer the study medication correctly. Subject must be willing and able to complete the electronic diary card with each pain episode. Signed consent must be obtained at screening prior to any procedures being performed. Exclusion Criteria: Psychiatric/cognitive or neurological impairment that would limit the subject's ability to understand or complete the diary Cardiopulmonary disease that, in the opinion of the investigator, would significantly increase the risk of respiratory depression Recent history or current evidence of alcohol or other drug substance (licit or illicit) abuse Rapidly escalating pain that the investigator believes may require an increase in the dosage of background pain medication during the study Moderate (Grade 3) to severe (Grade 4) mucositis (Subjects with less than moderate mucositis are permitted and must be instructed to not apply the BEMA disc at a site of inflammation.) Strontium 89 therapy within the previous 6 months Any other therapy prior to the study that the investigator considers could alter pain or the response to pain medication. Use of an investigational drug within 4 weeks preceding this study History of hypersensitivity or intolerance to fentanyl Regularly more than 4 episodes per day Eastern Cooperative Oncology Group (ECOG) performance status of 4 or 5 Subject is pregnant, actively trying to become pregnant, breast feeding or not using adequate contraceptive measures

Ages Eligible for Study
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Minimum 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: BEMA™<br>* BioDelivery Sciences International, Inc. (BDSI) has developed BioErodible MucoAdhesive (BEMA) Fentanyl, an alternative product to OTFC that does not require the subject to continuously paint the inside of the mouth with the dosage form. The BDSI product is a small soluble film that is placed against the mucosal membrane inside the mouth. The mucoadhesive polymers in the film readily adhere to the mucosal membrane (within 5 seconds) when moistened. The components of the film are water soluble, so the entire dosage form dissolves within 30 minutes of application.<br>* Other names: Onsolis (fentanyl buccal soluble film);Drug: Placebo<br> <br> |
| Experimental: BEMA™ Fentanyl<br>BioErodible MucoAdhesive (BEMA) Fentanyl | Drug: BEMA™<br>* BioDelivery Sciences International, Inc. (BDSI) has developed BioErodible MucoAdhesive (BEMA) Fentanyl, an alternative product to OTFC that does not require the subject to continuously paint the inside of the mouth with the dosage form. The BDSI product is a small soluble film that is placed against the mucosal membrane inside the mouth. The mucoadhesive polymers in the film readily adhere to the mucosal membrane (within 5 seconds) when moistened. The components of the film are water soluble, so the entire dosage form dissolves within 30 minutes of application.<br>* Other names: Onsolis (fentanyl buccal soluble film);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Pain Intensity Differences (SPID) | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. The primary endpoint was the Summary of Pain Intensity Differences at 30 minutes after dosing (SPID 30) in ITT population for Onsolis versus placebo during double-blind period of study. SPID was calculated as a weighted sum of the PID of all time points at or before time point of interest.Range of possible SPID values is -10X time point (minutes) to 10X time point (minutes). Higher value indicates a better outcome. | 0-30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SPID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. The primary endpoint was the Summary of Pain Intensity Differences at 30 minutes after dosing (SPID 30) in ITT population for Onsolis versus placebo during double-blind period of study. SPID was calculated as a weighted sum of the PID of all time points at or before time point of interest.Range of possible SPID values is -10X time point (minutes) to 10X time point (minutes). Higher value indicates a better outcome.SPID was calculated as a weighted sum of the pain intensity difference of all time points at or before the time point of interest. | 0-5 minutes | 
| SPID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. The primary endpoint was the Summary of Pain Intensity Differences at 30 minutes after dosing (SPID 30) in ITT population for Onsolis versus placebo during double-blind period of study. SPID was calculated as a weighted sum of the PID of all time points at or before time point of interest.Range of possible SPID values is -10X time point (minutes) to 10X time point (minutes). Higher value indicates a better outcome.SPID was calculated as a weighted sum of the pain intensity difference of all time points at or before the time point of interest. | 0-10 minutes | 
| SPID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. The primary endpoint was the Summary of Pain Intensity Differences at 30 minutes after dosing (SPID 30) in ITT population for Onsolis versus placebo during double-blind period of study. SPID was calculated as a weighted sum of the PID of all time points at or before time point of interest.Range of possible SPID values is -10X time point (minutes) to 10X time point (minutes). Higher value indicates a better outcome.SPID was calculated as a weighted sum of the pain intensity difference of all time points at or before the time point of interest. | 0-15 minutes | 
| SPID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. The primary endpoint was the Summary of Pain Intensity Differences at 30 minutes after dosing (SPID 30) in ITT population for Onsolis versus placebo during double-blind period of study. SPID was calculated as a weighted sum of the PID of all time points at or before time point of interest.Range of possible SPID values is -10X time point (minutes) to 10X time point (minutes). Higher value indicates a better outcome.SPID was calculated as a weighted sum of the pain intensity difference of all time points at or before the time point of interest. | 0-45 minutes | 
| SPID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. The primary endpoint was the Summary of Pain Intensity Differences at 30 minutes after dosing (SPID 30) in ITT population for Onsolis versus placebo during double-blind period of study. SPID was calculated as a weighted sum of the PID of all time points at or before time point of interest.Range of possible SPID values is -10X time point (minutes) to 10X time point (minutes). Higher value indicates a better outcome.SPID was calculated as a weighted sum of the pain intensity difference of all time points at or before the time point of interest. | 0-60 minutes | 
| PID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. | 5 minutes after dosing | 
| PID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. | 10 minutes after dosing | 
| PID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. | 15 minutes after dosing | 
| PID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. | 30 minutes after dosing | 
| PID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. | 45 minutes after dosing | 
| PID | Pain intensity (using an 11-point [0 = no pain to 10 = worst pain] numeric scale) was recorded at 0, 5, 10, 15, 30, 45, and 60 minutes after dosing. Pain intensity difference (PID) was defined as the baseline pain score minus the pain score of each time point. | 60 minutes after dosing | 
| Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief) at 5, 10, 15, 30, 45, and 60 minutes after taking the study medication or until rescue. | 5 minutes after dosing | 
| Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief) at 5, 10, 15, 30, 45, and 60 minutes after taking the study medication or until rescue. | 10 minutes after dosing | 
| Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief) at 5, 10, 15, 30, 45, and 60 minutes after taking the study medication or until rescue. | 15 minutes after dosing | 
| Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief) at 5, 10, 15, 30, 45, and 60 minutes after taking the study medication or until rescue. | 30 minutes after dosing | 
| Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief) at 5, 10, 15, 30, 45, and 60 minutes after taking the study medication or until rescue. | 45 minutes after dosing | 
| Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief) at 5, 10, 15, 30, 45, and 60 minutes after taking the study medication or until rescue. | 60 minutes after dosing | 
| Total Pain Relief | Total Pain Relief (TOTPAR) is calculated as the weighted sum of the pain relief (PR) of all time points at or prior to the time point of interest.Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief)compared to baseline (pre-dose) | 5 minutes | 
| Total Pain Relief | Total Pain Relief (TOTPAR) is calculated as the weighted sum of the pain relief (PR) of all time points at or prior to the time point of interest. Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief)compared to baseline (pre-dose) | 10 minutes | 
| Total Pain Relief | Total Pain Relief (TOTPAR) is calculated as the weighted sum of the pain relief (PR) of all time points at or prior to the time point of interest. Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief)compared to baseline (pre-dose) | 15 minutes | 
| Total Pain Relief | Total Pain Relief (TOTPAR) is calculated as the weighted sum of the pain relief (PR) of all time points at or prior to the time point of interest. Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief)compared to baseline (pre-dose) | 30 minutes | 
| Total Pain Relief | Total Pain Relief (TOTPAR) is calculated as the weighted sum of the pain relief (PR) of all time points at or prior to the time point of interest. Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief)compared to baseline (pre-dose) | 45 minutes | 
| Total Pain Relief | Total Pain Relief (TOTPAR) is calculated as the weighted sum of the pain relief (PR) of all time points at or prior to the time point of interest. Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief)compared to baseline (pre-dose) | 60 minutes | 
| Subject Overall Satisfaction With Study Drug | Subjects evaluated their overall satisfaction with study drug at the time rescue medication was consumed or at the 60-minute time point using a 5-point categorical scale (0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent). | 60 minutes or at time of rescue medication use | 
| Percentage of Pain Free Episodes | A pain free episode is one with 0 pain intensity at the specified time point. Percentage of episodes that are pain-free per subject is analyzed. | 5 minutes | 
| Percentage of Pain Free Episodes | A pain free episode is one with 0 pain intensity at the specified time point. Percentage of episodes that are pain-free per subject is analyzed. | 10 minutes | 
| Percentage of Pain Free Episodes | A pain free episode is one with 0 pain intensity at the specified time point. Percentage of episodes that are pain-free per subject is analyzed. | 15 minutes | 
| Percentage of Pain Free Episodes | A pain free episode is one with 0 pain intensity at the specified time point. Percentage of episodes that are pain-free per subject is analyzed. | 30 minutes | 
| Percentage of Pain Free Episodes | A pain free episode is one with 0 pain intensity at the specified time point. Percentage of episodes that are pain-free per subject is analyzed. | 45 minutes | 
| Percentage of Pain Free Episodes | A pain free episode is one with 0 pain intensity at the specified time point. Percentage of episodes that are pain-free per subject is analyzed. | 60 minutes | 
| Episodes With at Least 50% Decreases in Pain | Number of episodes where the total pain score has at least a 50% reduction from baseline. | 15 minutes | 
| Episodes With at Least 50% Decreases in Pain | Number of episodes where the total pain score has at least a 50% reduction from baseline. | 30 minutes | 
| Episodes With at Least 50% Decreases in Pain | Number of episodes where the total pain score has at least a 50% reduction from baseline. | 45 minutes | 
| Episodes With at Least 50% Decreases in Pain | Number of episodes where the total pain score has at least a 50% reduction from baseline. | 60 minutes | 
| Episodes With at Least 33% Decreases in Pain | Number of episodes where the total pain score has at least a 33% reduction from baseline. | 15 minutes | 
| Episodes With at Least 33% Decreases in Pain | Number of episodes where the total pain score has at least a 33% reduction from baseline. | 30 minutes | 
| Episodes With at Least 33% Decreases in Pain | Number of episodes where the total pain score has at least a 33% reduction from baseline. | 45 minutes | 
| Episodes With at Least 33% Decreases in Pain | Number of episodes where the total pain score has at least a 50% reduction from baseline. | 60 minutes | 
| Episodes With Complete Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief). Percentage of episodes with complete relief per subject is analyzed where a complete pain relief episode is defined as pain relief of value 4 at the specified time point. | 5 minutes | 
| Episodes With Complete Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief).Percentage of episodes with complete relief per subject is analyzed where a complete pain relief episode is defined as pain relief of value 4 at the specified time point. | 10 minutes | 
| Episodes With Complete Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief).Percentage of episodes with complete relief per subject is analyzed where a complete pain relief episode is defined as pain relief of value 4 at the specified time point. | 15 minutes | 
| Episodes With Complete Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief). Percentage of episodes with complete relief per subject is analyzed where a complete pain relief episode is defined as pain relief of value 4 at the specified time point. | 30 minutes | 
| Episodes With Complete Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief). Percentage of episodes with complete relief per subject is analyzed where a complete pain relief episode is defined as pain relief of value 4 at the specified time point. | 45 minutes | 
| Episodes With Complete Pain Relief | Pain relief (PR) is measured using a 5-point categorical scale (0=no relief to 4=complete relief). Percentage of episodes with complete relief per subject is analyzed where a complete pain relief episode is defined as pain relief of value 4 at the specified time point. | 60 minutes | 
| Rescue Medication Usage | Rescue medication is medication taken if adequate pain relief is not realized within 30 minutes following application of the study drug. Percentage of episodes when rescue medication was used per subject is analyzed. | 28 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breakthrough Pain in Patients with Cancer