Study of Breakthrough Cancer Pain: Assessment of Fentanyl Buccal Tablets Titration and Treatment in Opioid-Tolerant Patients

A European Multicenter Open-Label Study of Breakthrough Cancer Pain: Assessment of Fentanyl Buccal Tablets Titration and Treatment in Opioid-Tolerant Patients

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00842829

Enrollment

330

Registered

2009-02-12

Start date

2009-01-31

Completion date

2011-05-31

Last updated

2012-10-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breakthrough Pain, Cancer Pain

Keywords

Breakthrough Cancer Pain

Brief summary

Breakthrough cancer pain (BTcP) is a common problem in patients with cancer. Fentanyl Buccal Tablet (FBT) is used for the treatment of BTP in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain. FBT treatment should be individually titrated to an effective dose that provides adequate analgesia and minimizes undesirable effects. To reach the safest effective dose for the individual patient as soon as possible, the dose titration process is critical. The aim of this study, conducted under pragmatic conditions in a large-scale population of cancer patients is to compare the proportion of patients reaching an effective FBT dose after titration starting with either a 100 mcg dose or a 200 mcg dose.

Interventions

DRUGFentanyl Buccal Tablet (FBT)

FBTs were self-administered by participants via the oral mucosa. During the open-label dose titration period, participants used 1 to 4 tablets of the 100 mcg or 200 mcg strength to individually titrate upwards to an effective dose through the range of available strengths (i.e. 100, 200, 400, 600, or 800 mcg). For the open-label treatment and continuation periods, single dose tablets at the effective dose identified during the titration period were used. The maximum dose allowed per breakthrough pain (BTP) episode was 800 mcg. On any single day, participants were not to use FBT for more than 4 BTP episodes.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* The patient is willing to provide written informed consent to participate in this study. * The patient can be either an out-patient or an in-patient. * The patient has a histologically documented diagnosis of cancer. * The patient has stable background pain due to cancer. * The patient experiences up to 4 BTcP episodes per 24 hours. * As maintenance opioid therapy, the patient is currently taking 1 of the following: at least 60 mg of oral morphine/day, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone/day, at least 8 mg of hydromorphone/day, of an equianalgesic dose of another opioid for a week or longer before administration of the first dose of study drug. * Women of childbearing potential, using a medically accepted, highly effective method of birth control and agree to continued use of this method for the duration of the study. * The patient must be willing and able to successfully self-administer the study drug and to fill in study documents.

Exclusion criteria

* The patient is without maintenance opioid therapy. * The patient has uncontrolled or rapidly escalating pain as determined by the investigator. * The patient has known or suspected hypersensitivities, allergies, or other contraindications to the active drug or to any of the excipients of the study drug. * The patient has respiratory depression or chronic obstructive pulmonary disease, or any other medical condition predisposing to respiratory depression. * The patient has medical or psychiatric disease that, in the opinion of the investigator, would compromise collected data. * The patient is expected to have surgery during the study. * The patient is pregnant or lactating. * The patient has participated in a study involving an investigational drug in the prior 30 days. * The patient has received a monoamine oxidase inhibitor (MAOI) within 14 days before the first treatment with study drug. * The patient has any other medical condition or is receiving concomitant medication/therapy (e.g., regional nerve block) that could, in the opinion of the investigator, compromise the patient's safety or compliance with the study protocol, or compromise collected data.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants Reaching an Effective Fentanyl Buccal Tablet (FBT) Dose As Assessed by the Participant During the Titration Period	Day 1 up to Day 7	The effective dose was the dose that, for 2 consecutive break-through pain (BTP) episodes, provided adequate analgesia within the first 30 minutes after administration of study drug and that minimized undesirable effects. The assessment was performed by the participant and was reported in the titration-period diary. The next BTP episode was used to confirm the effective dose, and if confirmed, the effective dose was used for all following BTP episodes.

Secondary

Measure	Time frame	Description
Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	Day 1 up to Day 7	Number of participants for which an effective dose of FBT was reached as judged by each participant. The effective dose was the dose that, for 2 consecutive break-through pain (BTP) episodes, provided adequate analgesia within the first 30 minutes after administration of study drug and that minimized undesirable effects. The assessment was performed by the participant and was reported in the titration-period diary. The next BTP episode was used to confirm the effective dose, and if confirmed, the effective dose was used for all following BTP episodes.
Breakthrough Pain (BTP) Episodes Requiring the Use of Rescue Medication During the Titration Period and the Treatment Period	Days 1 to up to Day 7 (Titration Period); approximately Day 8 up to Day 15 (Treatment Period)	The number of breakthrough pain (BTP) episodes in which the participant did not obtain effective pain relief from study medication and took a rescue medication.
Participant Assessment of Medication Performance During the Treatment Period	approximately Day 8-15	Participants assessed the performance of FBT at 30 minutes and 60 minutes after dosing each episode during the treatment period. For each episode, the participant answered the question 'How well did your study medication perform in controlling the breakthrough pain episode?' on a 5-point Likert-type scale (poor=0, fair=1, good=2, very good=3, and excellent=4).
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: General Activity	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses general activity.
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Mood	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses mood.
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Walking Ability	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses walking ability.
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Normal Work	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses normal work.
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Relations With Other People	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses relations with other people.
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Sleep	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses sleep.
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Enjoyment of Life	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses enjoyment of life.
Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire: Global Score	Day 0 (baseline), approximately Day 15 (end of Treatment Period)	Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. The Global Score is the sum of the subscales (total scale is 0-70). A negative change from baseline represents an improvement.
Kaplan-Meier Estimates for Time to Meaningful Pain Relief As Assessed by Participants During the Treatment Period For Overall Breakthrough Pain (BTP) Episodes	approximately Day 8-15	Overall episode data analyzed all values of time to meaningful pain relief taken over all BTP episodes during the treatment period. If meaningful pain relief was not achieved within 60 minutes of FBT intake, or if rescue medication was taken, the event was censored. Meaningful pain relief was left to the judgment of participants, who used a stopwatch and recorded the time from treatment until pain relief in a patient diary.
Participant's Global Assessment of Satisfaction (Does This BTP Medication Relieve Your Pain Quickly so You Can Get Back to Sleep?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Does this BTP medication relieve your pain quickly so you can get back to sleep?, were captured on a five-point scale from 0=not at all to 4=very much.
Participant's Global Assessment of Satisfaction (Does This Medication Work Fast?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Does this medication work fast?, were captured on a five-point scale from 0=not at all to 4=very much.
Participant's Global Assessment of Satisfaction (Does This Medication Provide Adequate Relief?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Does this medication provide adequate relief?, were captured on a five-point scale from 0=not at all to 4=very much.
Participant's Global Assessment of Satisfaction (Is This Medication Easy to Take?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Is this medication easy to take?, were captured on a five-point scale from 0=not at all to 4=very much.
Participant's Global Assessment of Satisfaction (Do You Find This Medication Comfortable to Take in Public?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Do you find this medication comfortable to take in public?, were captured on a five-point scale from 0=not at all to 4=very much.
Participant's Global Assessment of Satisfaction (Do You Feel Safe Taking This Medication?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Do you feel safe taking this medication?, were captured on a five-point scale from 0=not at all to 4=very much.
Participant's Global Assessment of Satisfaction (Do You Understand the Instructions?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Do you understand the instructions?, were captured on a five-point scale from 0=not at all to 4=very much.
Participant's Global Assessment of Ease of Use at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Ease of use was assessed using the question 'Did you find this treatment easy/convenient to use for treatment of your breakthrough pain episodes?'. The answer was based on a 4-point numerical scale (0=Poor, 1=Fair, 2=Easy, 3=Very Easy). This assessment was performed at the end of the Treatment Period (or early termination).
Participant's Global Impression of Change at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Global impression of change was assessed using the question 'Since the start of the study, my overall status is?'. The answer was based on a 7-point scale (1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse, and 7=Very much worse). This assessment was performed at the end of the Treatment Period (or early termination).
Participants With Adverse Events (AE) Summarized by Treatment Period	Day 1-7 (Titration Period). Day 8-15 (Treatment Period), Days 16-688 (Continuation Period)	Participants with treatment-emergent adverse events are summarized by each treatment period. Relation to study drug was assessed by the investigator. The 'Any AE' category below includes serious adverse events.
Participant's Global Assessment of Satisfaction (Satisfied With BTP Treatment?) at the End of the Treatment Period	approximately Day 15 (end of Treatment Period)	Responses to the Patient Satisfaction questionnaire question, Satisfied with the BTP Treatment?, were captured on a five-point scale from 0=not at all to 4=very much.

Countries

France, Germany, Ireland, Italy, Poland, Spain, United Kingdom

Participant flow

Recruitment details

A total of 442 patients already receiving opioid maintenance therapy for chronic cancer pain and experiencing up to 4 BTP episodes per 24 hours (on average) were screened at 135 centers in 7 European countries.

Participants by arm

Arm	Count
FBT 100 Mcg - Dose Titration Period During the Titration Period, participants took fentanyl buccal tables (FBT) with a starting dose of 100 mcg until they reached an effective dose, with a maximum dose of 800 mcg and a maximum timeframe of 7 days.	156
FBT 200 Mcg - Dose Titration Period During the Titration Period, participants took fentanyl buccal tables (FBT) with a starting dose of 200 mcg until they reached an effective dose, with a maximum dose of 800 mcg and a maximum timeframe of 7 days.	174
Total	330

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Continuation Period	Adverse Event	0	0	32
Continuation Period	Lack of Efficacy	0	0	6
Continuation Period	Non-compliance to study drug	0	0	1
Continuation Period	Non-compliance to study procedures	0	0	2
Continuation Period	Other	0	0	7
Continuation Period	Unstable persistent cancer pain	0	0	3
Continuation Period	Withdrawal by Subject	0	0	10
Dose Titration Period	Adverse Event	11	10	0
Dose Titration Period	Lack of Efficacy	4	1	0
Dose Titration Period	Non-compliance to study drug	2	1	0
Dose Titration Period	Non-compliance to study procedures	1	1	0
Dose Titration Period	Other	5	4	0
Dose Titration Period	Unstable persistent cancer pain	1	0	0
Dose Titration Period	Withdrawal by Subject	2	6	0
Treatment Period	Adverse Event	0	0	15
Treatment Period	Consistently >4 BTP episodes daily	0	0	1
Treatment Period	Lack of Efficacy	0	0	6
Treatment Period	Non-compliance to study procedures	0	0	4
Treatment Period	Other	0	0	18
Treatment Period	Protocol Violation	0	0	2
Treatment Period	Unclear completion status	0	0	1
Treatment Period	Unstable persistent cancer pain	0	0	5
Treatment Period	Withdrawal by Subject	0	0	11

Baseline characteristics

Characteristic	FBT 100 Mcg - Dose Titration Period	FBT 200 Mcg - Dose Titration Period	Total
Age Continuous	59.5 years STANDARD_DEVIATION 11.72	60.1 years STANDARD_DEVIATION 10.97	59.8 years STANDARD_DEVIATION 11.32
Cancer Site Breast	31 participants	36 participants	67 participants
Cancer Site Colon/rectum	15 participants	25 participants	40 participants
Cancer Site Colon/rectum + Pancreas/stomach + other	1 participants	0 participants	1 participants
Cancer Site Head/neck	12 participants	12 participants	24 participants
Cancer Site Leukemia/lymphoma	2 participants	4 participants	6 participants
Cancer Site Lung	26 participants	21 participants	47 participants
Cancer Site Myeloma	5 participants	4 participants	9 participants
Cancer Site Oesophageal	4 participants	2 participants	6 participants
Cancer Site Other (not specified)	39 participants	42 participants	81 participants
Cancer Site Pancreas/stomach	13 participants	11 participants	24 participants
Cancer Site Prostate	8 participants	17 participants	25 participants
Region of Enrollment France	16 participants	25 participants	41 participants
Region of Enrollment Germany	32 participants	38 participants	70 participants
Region of Enrollment Ireland	1 participants	0 participants	1 participants
Region of Enrollment Italy	35 participants	37 participants	72 participants
Region of Enrollment Poland	38 participants	41 participants	79 participants
Region of Enrollment Spain	26 participants	26 participants	52 participants
Region of Enrollment United Kingdom	8 participants	7 participants	15 participants
Sex: Female, Male Female	71 Participants	78 Participants	149 Participants
Sex: Female, Male Male	85 Participants	96 Participants	181 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	52 / 312
serious Total, serious adverse events	67 / 312

Outcome results

Primary

Percentage of Participants Reaching an Effective Fentanyl Buccal Tablet (FBT) Dose As Assessed by the Participant During the Titration Period

The effective dose was the dose that, for 2 consecutive break-through pain (BTP) episodes, provided adequate analgesia within the first 30 minutes after administration of study drug and that minimized undesirable effects. The assessment was performed by the participant and was reported in the titration-period diary. The next BTP episode was used to confirm the effective dose, and if confirmed, the effective dose was used for all following BTP episodes.

Time frame: Day 1 up to Day 7

Population: Titration safety analysis set consisting of participants who took at least one dose of study medication.

Arm	Measure	Value (NUMBER)
FBT 100 Mcg - Dose Titration Period	Percentage of Participants Reaching an Effective Fentanyl Buccal Tablet (FBT) Dose As Assessed by the Participant During the Titration Period	75.2 percentage of treated participants
FBT 200 Mcg - Dose Titration Period	Percentage of Participants Reaching an Effective Fentanyl Buccal Tablet (FBT) Dose As Assessed by the Participant During the Titration Period	81.2 percentage of treated participants

Comparison: Treatment comparison difference (100 mcg - 200 mcg)

Secondary

Breakthrough Pain (BTP) Episodes Requiring the Use of Rescue Medication During the Titration Period and the Treatment Period

The number of breakthrough pain (BTP) episodes in which the participant did not obtain effective pain relief from study medication and took a rescue medication.

Time frame: Days 1 to up to Day 7 (Titration Period); approximately Day 8 up to Day 15 (Treatment Period)

Population: Safety analysis set consisting of participants who took at least one dose of study drug during the relevant study period.

Arm	Measure	Value (NUMBER)
FBT 100 Mcg - Dose Titration Period	Breakthrough Pain (BTP) Episodes Requiring the Use of Rescue Medication During the Titration Period and the Treatment Period	102 BTP episodes
FBT 200 Mcg - Dose Titration Period	Breakthrough Pain (BTP) Episodes Requiring the Use of Rescue Medication During the Titration Period and the Treatment Period	153 BTP episodes

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire: Global Score

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. The Global Score is the sum of the subscales (total scale is 0-70). A negative change from baseline represents an improvement.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire: Global Score	-8.6 units on a scale	Standard Deviation 13.47

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Enjoyment of Life

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses enjoyment of life.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Enjoyment of Life	-1.5 units on a scale	Standard Deviation 2.77

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: General Activity

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses general activity.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: General Activity	-1.0 units on a scale	Standard Deviation 2.52

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Mood

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses mood.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Mood	-1.4 units on a scale	Standard Deviation 2.55

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Normal Work

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses normal work.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Normal Work	-1.3 units on a scale	Standard Deviation 2.61

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Relations With Other People

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses relations with other people.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Relations With Other People	-1.2 units on a scale	Standard Deviation 2.5

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Sleep

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses sleep.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Sleep	-1.4 units on a scale	Standard Deviation 2.66

Secondary

Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Walking Ability

Participants completed the BPI-7S questionnaire to indicate their quality of life and functional status between study time points. For each subscale, the participant rated their responses from 0=Does not interfere through to 10=Completely interferes. A negative change from baseline represents an improvement. This subscale assesses walking ability.

Time frame: Day 0 (baseline), approximately Day 15 (end of Treatment Period)

Population: Safety analysis set of participants with both baseline and Treatment Period responses

Arm	Measure	Value (MEAN)	Dispersion
FBT 100 Mcg - Dose Titration Period	Change From Baseline to End of Treatment Period (Approximately Day 15) in the Brief Pain Inventory 7-item (BPI-7S) Questionnaire Subscale: Walking Ability	-0.9 units on a scale	Standard Deviation 2.29

Secondary

Kaplan-Meier Estimates for Time to Meaningful Pain Relief As Assessed by Participants During the Treatment Period For Overall Breakthrough Pain (BTP) Episodes

Overall episode data analyzed all values of time to meaningful pain relief taken over all BTP episodes during the treatment period. If meaningful pain relief was not achieved within 60 minutes of FBT intake, or if rescue medication was taken, the event was censored. Meaningful pain relief was left to the judgment of participants, who used a stopwatch and recorded the time from treatment until pain relief in a patient diary.

Time frame: approximately Day 8-15

Population: Safety analysis set consisting of participants who received at least one dose of study drug during the Treatment Period, and who recorded the time to pain relief in the patient diary.

Arm	Measure	Value (MEDIAN)
FBT 100 Mcg - Dose Titration Period	Kaplan-Meier Estimates for Time to Meaningful Pain Relief As Assessed by Participants During the Treatment Period For Overall Breakthrough Pain (BTP) Episodes	19.00 minutes

Secondary

Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period

Number of participants for which an effective dose of FBT was reached as judged by each participant. The effective dose was the dose that, for 2 consecutive break-through pain (BTP) episodes, provided adequate analgesia within the first 30 minutes after administration of study drug and that minimized undesirable effects. The assessment was performed by the participant and was reported in the titration-period diary. The next BTP episode was used to confirm the effective dose, and if confirmed, the effective dose was used for all following BTP episodes.

Time frame: Day 1 up to Day 7

Population: Titration safety analysis set consisting of participants who took at least one dose of study medication.

Arm	Measure	Group	Value (NUMBER)
FBT 100 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	300 mcg (evaluated by mistake)	1 participants
FBT 100 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	600 mcg	8 participants
FBT 100 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	200 mcg	38 participants
FBT 100 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	800 mcg	5 participants
FBT 100 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	400 mcg	23 participants
FBT 100 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	Missing	36 participants
FBT 100 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	100 mcg	34 participants
FBT 200 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	Missing	31 participants
FBT 200 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	100 mcg	7 participants
FBT 200 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	200 mcg	61 participants
FBT 200 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	300 mcg (evaluated by mistake)	1 participants
FBT 200 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	400 mcg	42 participants
FBT 200 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	600 mcg	15 participants
FBT 200 Mcg - Dose Titration Period	Number of Participants Reaching An Effective Dose As Assessed by the Participant During the Titration Period	800 mcg	10 participants

Secondary

Participant Assessment of Medication Performance During the Treatment Period

Participants assessed the performance of FBT at 30 minutes and 60 minutes after dosing each episode during the treatment period. For each episode, the participant answered the question 'How well did your study medication perform in controlling the breakthrough pain episode?' on a 5-point Likert-type scale (poor=0, fair=1, good=2, very good=3, and excellent=4).

Time frame: approximately Day 8-15

Population: Safety analysis set of participants with a response at the time point (30 or 60 minutes) post dose.

Arm	Measure	Group	Value (NUMBER)
FBT 100 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Excellent	103 BTP episodes
FBT 100 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Very good	433 BTP episodes
FBT 100 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Good	712 BTP episodes
FBT 100 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Fair	428 BTP episodes
FBT 100 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Poor	100 BTP episodes
FBT 100 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Missing	35 BTP episodes
FBT 200 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Poor	49 BTP episodes
FBT 200 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Excellent	144 BTP episodes
FBT 200 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Fair	245 BTP episodes
FBT 200 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Very good	584 BTP episodes
FBT 200 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Missing	143 BTP episodes
FBT 200 Mcg - Dose Titration Period	Participant Assessment of Medication Performance During the Treatment Period	Good	646 BTP episodes

Secondary

Participant's Global Assessment of Ease of Use at the End of the Treatment Period

Ease of use was assessed using the question 'Did you find this treatment easy/convenient to use for treatment of your breakthrough pain episodes?'. The answer was based on a 4-point numerical scale (0=Poor, 1=Fair, 2=Easy, 3=Very Easy). This assessment was performed at the end of the Treatment Period (or early termination).