Break Through Pain, Cancer
Conditions
Keywords
Break through pain, BTP, Cancer, Intranasal Fentanyl Spray, INFS, cancer patients
Brief summary
The aim of this clinical trial was to demonstrate the efficacy of a 400 μg dose strength of intranasal fentanyl spray (INFS, Instanyl®) and to evaluate the safety and to establish long term tolerability of treatment with INFS doses of 50, 100, 200 and 400 μg.
Detailed description
This is a clinical trial with 12 weeks treatment of Intranasal fentanyl (INFS) in cancer patients with breakthrough pain (BTP). It was composed of a dose titrated, placebo-controlled, double-blind, randomised, cross-over efficacy phase, combined with a titration and a tolerability phase assessing the safety and nasal tolerability of INFS. The trial is set up with a screening period and three treatment phases: a titration phase (I), an efficacy phase (II) and a tolerability phase (III). The entire trial period for each completed patient consisted of the one week screening period and 12 weeks treatment with INFS.
Interventions
DRUGIntranasal Fentanyl Spray (INFS)
Applied as 1 puff (= 1 dose) in one nostril, or applied as two puffs (= 2 doses, 1 in each nostril) with ten minutes apart.
DRUGPlacebo
Matching intranasal placebo spray
Sponsors
Takeda
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
All inclusion criteria were answered 'yes' for a patient to participate in the clinical trial. * Is the patient a cancer patient with breakthrough Pain (BTP)? * Has the patient received either oral opioids or transdermal fentanyl for treatment of background pain (BGP) within the last month prior to the screening visit? * Is the current dose of prescribed opioids (for BGP) equivalent to 60-1000 mg oral morphine/day? * Has the patient's BGP for the last 7 days prior to the screening visit been generally stable, and on average controlled to a mild level (defined as ≤ 4 on the 11-point Numerical Rating Scale \[NRS\])? * Does the patient (at the time of the screening visit) experience his/her current BTP episodes to be of such severe pain intensity, that he/she in general needs additional analgesia (i.e. on top of the background opioid treatment)? * Has the patient on average for the last 7 days prior to the screening visit had at least three BTP episodes per week, but no more than four BTP episodes per day? * Is the patient able to use intranasal drugs? * Is the life expectancy of the patient at least 3 months from the date of the screening visit?
Exclusion criteria
1. Has the patient had an illicit substance abuse within the last year prior to screening? 2. Does the patient have severe hepatic impairment? - defined as alanine aminotransferase (ALT or) aspartate aminotransferase (AST) levels \> 3x upper limit of normal (ULN) 3. Does the patient have severe renal impairment? - defined as serum creatinine ≥ 3.0 mg/dl (265 micromol/L) 4. Has the patient ever had facial radiotherapy or is the patient scheduled to facial radiotherapy? 5. Has the patient been treated with any monoamine oxidase (MAO) inhibitors within the last 14 days prior to the screening visit? 6. Does the patient have severe impaired respiratory function, which may increase the risk of clinically relevant respiratory depression by BTP fentanyl treatment? 7. Is the patient known to be hypersensitive to fentanyl or to other opioids or any of their excipients? 8. Does the patient have any head injury, primary brain tumor or other pathological conditions, which could significantly increase the risk of increased intracranial pressure or impaired consciousness?
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment | During the efficacy phase (II), at each episode of breakthrough pain, at 0 and 10 minutes after first dose of study drug. | During the efficacy phase participants assessed their pain intensity at each breakthrough pain (BTP) episode at 0 and 10 minutes after first dose using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. PID10 is calculated as the difference in pain intensity from time 0 to 10 minutes. A positive value is a decrease (improvement) of the pain; a ≥ 2-point difference is considered as clinically important. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug | During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug. | During the efficacy phase participants assessed their pain intensity at each breakthrough pain (BTP) episode at 0, 5, 30 and 60 minutes after first dose using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. PID is calculated as the difference in pain intensity from time 0 to each time point. A positive value is a decrease (improvement) of the pain; a ≥ 2-point difference is considered as clinically important. |
| Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores | During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug | The SPID30 and SPID60 represent the average improvement in pain intensity over the 30 minute interval and 60 minute interval, respectively. SPIDt was calculated as the area under the curve (AUC) for Pain Intensity Difference over the time interval 0 to t minutes, respectively, divided by the length of the time interval (t minutes). A positive value is a decrease (improvement) of the pain. Pain intensity was assessed at 0, 5, 30 and 60 minutes after study drug using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. PID is calculated as the difference in pain intensity from time 0 to each time point. |
| Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug | Overall responder rate is defined as the proportion of breakthrough pain (BTP) episodes with a positive response to treatment. The following definitions of a positive response were analyzed: • greater than or equal to 1 point reduction in pain intensity (PI) from time 0, • greater than or equal to 2 point reduction in PI from time 0, and • greater than or equal to 3 point reduction in PI from time 0. Pain intensity was assessed using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. |
| Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Baseline and at 12 weeks | Medical examination of the nasal cavity by rhinoscopy was performed by an oto-rhino-laryngologist before the start of study treatment and at 12 weeks. Signs and any abnormalities were observed for each nostril using the following 4 points assessment scale: • 0 =not present; • 1 =present in a mild degree; • 2 =present in a moderate degree; • 3 =present in a severe degree. A difference in score of 1 or more from Baseline to the end of treatment represented a worsening, while a negative value indicated an improvement of the observed clinical sign. The oto-rhino-laryngologist also assessed whether worsening of a sign was related to study drug. Assessments for both left and right nostrils are presented together. The incidence is calculated as the number of assessments (n) in the improvement or worsening category divided by the number of assessments with a non-missing score for the Nasal Mucosa or Abnormality assessment. Only those signs or abnormalities with n\>0 were included |
| Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose | During the efficacy phase (II), at each episode of breakthrough pain, 60 minutes after first dose of study drug. | Participants assessed their general impression (GI) of treatment efficacy for treated BTP episodes at 60 minutes after first dose of study drug. The validated, categorical 5-point Verbal Rating Scale (VRS) was used for this assessment and scored as follows: * 0 =poor; * 1 =fair; * 2 =good; * 3 =very good; * 4 =excellent. |
| Number of Participants With Adverse Events (AEs) | 12 weeks | The severity (intensity of each AE was assessed as mild (transient symptoms, no interference with daily activities), moderate (marked symptoms, moderate interference with daily activities), or severe (considerable interference with daily activities) by the investigator. Serious adverse events are defined as any untoward medical occurrence that at any dose results in death or is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. The investigator assessed each AE as either related or not related to study treatment. |
| Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug | Overall responder rate is defined as the proportion of breakthrough pain (BTP) episodes with a positive response to treatment. The following definitions of a positive response were analyzed: • Greater than 33% reduction in PI from time 0; • Greater than or equal to 50% reduction in PI from time 0. Pain intensity was assessed using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. |
Countries
Hungary, Norway, Russia
Participant flow
Recruitment details
Participants took part in the study at 11 investigative sites in Hungary, Norway and Russia from 08 August 2011 to 04 January 2013.
Pre-assignment details
The first dose of Intranasal Fentanyl Spray (INFS) was taken at the clinic for training purposes and was not related to treatment of a BTP episode. One patient received the initial 50 μg test dose but did not receive INFS for titration, but is included in the safety analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Intranasal Fentanyl Spray (INFS) All participants were step-wise titrated to an effective dose of 50, 100, 200 or 400 μg INFS in the Titration Phase (I). Participants titrated to 200 or 400 μg INFS in the Titration Phase were randomized to an 8-spray sequence in the Efficacy Phase (II); 6 BTP episodes were treated with 400 μg INFS and 2 BTP episodes with placebo in a random sequence. Participants entered the Tolerability Phase (III) either directly from the Titration Phase (with an effective dose of 50 or 100 μg) or from the Efficacy Phase (400 μg) and continued with this specific dose, unless adjustment was needed, for a total treatment time of 12 weeks. | 46 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Efficacy Phase | Adverse Event | 1 |
| Efficacy Phase | Death | 1 |
| Titration Phase | Death | 1 |
| Titration Phase | Less than 3 BTP episodes per week | 2 |
| Titration Phase | Physician Decision | 1 |
| Titration Phase | Unsuccessful titration at any dose | 1 |
| Titration Phase | Withdrawal by Subject | 7 |
| Tolerability Phase | Adverse Event | 2 |
| Tolerability Phase | Death | 5 |
| Tolerability Phase | Other | 2 |
| Tolerability Phase | Physician Decision | 1 |
| Tolerability Phase | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Age, Continuous | 61.0 years STANDARD_DEVIATION 9.09 |
| Race/Ethnicity, Customized White | 46 participants |
| Region of Enrollment Hungary | 33 participants |
| Region of Enrollment Norway | 10 participants |
| Region of Enrollment Russian Federation | 3 participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 15 Participants |
| Site of Primary Tumour Reported in >5% Patients Breast | 14 participants |
| Site of Primary Tumour Reported in >5% Patients Colon/rectal | 3 participants |
| Site of Primary Tumour Reported in >5% Patients Female genital | 3 participants |
| Site of Primary Tumour Reported in >5% Patients Gastro-oesophageal | 1 participants |
| Site of Primary Tumour Reported in >5% Patients Liver | 1 participants |
| Site of Primary Tumour Reported in >5% Patients Lung respiratory system | 5 participants |
| Site of Primary Tumour Reported in >5% Patients Other | 1 participants |
| Site of Primary Tumour Reported in >5% Patients Pancreas | 6 participants |
| Site of Primary Tumour Reported in >5% Patients Prostate | 3 participants |
| Site of Primary Tumour Reported in >5% Patients Unknown Primary Tumour | 2 participants |
| Site of Primary Tumour Reported in >5% Patients Urological | 7 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 45 | 5 / 15 | 17 / 31 |
| serious Total, serious adverse events | 2 / 45 | 2 / 15 | 8 / 31 |
Outcome results
Primary
Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment
During the efficacy phase participants assessed their pain intensity at each breakthrough pain (BTP) episode at 0 and 10 minutes after first dose using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. PID10 is calculated as the difference in pain intensity from time 0 to 10 minutes. A positive value is a decrease (improvement) of the pain; a ≥ 2-point difference is considered as clinically important.
Time frame: During the efficacy phase (II), at each episode of breakthrough pain, at 0 and 10 minutes after first dose of study drug.
Population: The Full Analysis Set consisted of all randomly assigned participants who entered the Efficacy Phase (II) of the trial and were treated for at least 1 BTP episode with double-blind INFS in the Efficacy Phase of the trial.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment | 2.5 units on a scale |
| Placebo | Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment | 1.4 units on a scale |
p-value: 0.00295% CI: [0.41, 1.179]Mixed Models Analysis
Secondary
Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose
Participants assessed their general impression (GI) of treatment efficacy for treated BTP episodes at 60 minutes after first dose of study drug. The validated, categorical 5-point Verbal Rating Scale (VRS) was used for this assessment and scored as follows: * 0 =poor; * 1 =fair; * 2 =good; * 3 =very good; * 4 =excellent.
Time frame: During the efficacy phase (II), at each episode of breakthrough pain, 60 minutes after first dose of study drug.
Population: Efficacy Phase, Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose | 1.9 units on a scale |
| Placebo | Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose | 1.1 units on a scale |
Secondary
Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug
During the efficacy phase participants assessed their pain intensity at each breakthrough pain (BTP) episode at 0, 5, 30 and 60 minutes after first dose using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. PID is calculated as the difference in pain intensity from time 0 to each time point. A positive value is a decrease (improvement) of the pain; a ≥ 2-point difference is considered as clinically important.
Time frame: During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug.
Population: Efficacy Phase, Full Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug | PID at 5 minutes | 1.3 units on a scale |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug | PID at 30 minutes | 3.0 units on a scale |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug | PID at 60 minutes | 3.3 units on a scale |
| Placebo | Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug | PID at 5 minutes | 0.8 units on a scale |
| Placebo | Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug | PID at 30 minutes | 1.8 units on a scale |
| Placebo | Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug | PID at 60 minutes | 2.2 units on a scale |
Secondary
Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity
Overall responder rate is defined as the proportion of breakthrough pain (BTP) episodes with a positive response to treatment. The following definitions of a positive response were analyzed: • greater than or equal to 1 point reduction in pain intensity (PI) from time 0, • greater than or equal to 2 point reduction in PI from time 0, and • greater than or equal to 3 point reduction in PI from time 0. Pain intensity was assessed using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain.
Time frame: During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug
Population: Efficacy Phase, Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 5 minutes | 0.61 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 10 minutes | 0.74 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 30 minutes | 0.81 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 60 minutes | 0.86 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 5 minutes | 0.33 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 10 minutes | 0.51 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 30 minutes | 0.60 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 60 minutes | 0.65 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 5 minutes | 0.18 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 10 minutes | 0.32 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 30 minutes | 0.45 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 60 minutes | 0.50 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 30 minutes | 0.34 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 5 minutes | 0.45 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 30 minutes | 0.41 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 10 minutes | 0.55 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 10 minutes | 0.24 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 30 minutes | 0.66 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 60 minutes | 0.48 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 1 point reduction in PI at 60 minutes | 0.69 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 60 minutes | 0.48 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 5 minutes | 0.24 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 3 point reduction in PI at 5 minutes | 0.17 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity | ≥ 2 point reduction in PI at 10 minutes | 0.31 proportion of breakthrough pain episodes |
Secondary
Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity
Overall responder rate is defined as the proportion of breakthrough pain (BTP) episodes with a positive response to treatment. The following definitions of a positive response were analyzed: • Greater than 33% reduction in PI from time 0; • Greater than or equal to 50% reduction in PI from time 0. Pain intensity was assessed using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain.
Time frame: During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug
Population: Efficacy Phase, Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 5 minutes | 0.23 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 10 minutes | 0.44 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 30 minutes | 0.55 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 60 minutes | 0.58 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 5 minutes | 0.11 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 10 minutes | 0.31 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 30 minutes | 0.49 proportion of breakthrough pain episodes |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 60 minutes | 0.52 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 60 minutes | 0.34 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 5 minutes | 0.17 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 5 minutes | 0.07 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 10 minutes | 0.24 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 30 minutes | 0.31 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 30 minutes | 0.34 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | ≥ 50% reduction in PI at 10 minutes | 0.21 proportion of breakthrough pain episodes |
| Placebo | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity | > 33% reduction in PI at 60 minutes | 0.48 proportion of breakthrough pain episodes |
Secondary
Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores
The SPID30 and SPID60 represent the average improvement in pain intensity over the 30 minute interval and 60 minute interval, respectively. SPIDt was calculated as the area under the curve (AUC) for Pain Intensity Difference over the time interval 0 to t minutes, respectively, divided by the length of the time interval (t minutes). A positive value is a decrease (improvement) of the pain. Pain intensity was assessed at 0, 5, 30 and 60 minutes after study drug using the 11-point Numerical Rating Scale (NRS) on a scale from 0 to 10, where 0 represents the absence of pain and 10 is worst possible pain. PID is calculated as the difference in pain intensity from time 0 to each time point.
Time frame: During the efficacy phase (II) each episode of breakthrough pain, at 0, 5, 30 and 60 minutes after study drug
Population: Efficacy Phase, Full Analysis Set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores | SPID30 | 0.6 units on a scale |
| Intranasal Fentanyl Spray (INFS) | Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores | SPID60 | 0.7 units on a scale |
| Placebo | Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores | SPID30 | 0.4 units on a scale |
| Placebo | Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores | SPID60 | 0.5 units on a scale |
Secondary
Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score
Medical examination of the nasal cavity by rhinoscopy was performed by an oto-rhino-laryngologist before the start of study treatment and at 12 weeks. Signs and any abnormalities were observed for each nostril using the following 4 points assessment scale: • 0 =not present; • 1 =present in a mild degree; • 2 =present in a moderate degree; • 3 =present in a severe degree. A difference in score of 1 or more from Baseline to the end of treatment represented a worsening, while a negative value indicated an improvement of the observed clinical sign. The oto-rhino-laryngologist also assessed whether worsening of a sign was related to study drug. Assessments for both left and right nostrils are presented together. The incidence is calculated as the number of assessments (n) in the improvement or worsening category divided by the number of assessments with a non-missing score for the Nasal Mucosa or Abnormality assessment. Only those signs or abnormalities with n\>0 were included
Time frame: Baseline and at 12 weeks
Population: Safety Analysis Set, which included all patients who received at least 1 dose of INFS (including the initial test dose) with non-missing assessments.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Change of color: Improvement | 0.06 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Change of color: Worsening | 0.09 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Change of color: Worsening related to study drug | 0.09 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Inflammation: Improvement | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Inflammation: Worsening | 0.07 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Inflammation: Worsening related to study drug | 0.07 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Sore nose: Improvement | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Sore nose: Worsening | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Sore nose: Worsening related to study drug | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Ulceration: Improvement | NA proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Ulceration: Worsening | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Ulceration: Worsening related to study drug | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Dry nose: Improvement | 0.09 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Dry nose: Worsening | 0.06 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Dry nose: Worsening related to study drug | NA proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Runny nose: Improvement | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Runny nose: Worsening | 0.13 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Runny nose: Worsening related to study drug | 0.10 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Stuffed nose: Improvement | 0.06 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Stuffed nose: Worsening | 0.17 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Stuffed nose: Worsening related to study drug | 0.08 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Oedema: Improvement | 0.04 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Oedema: Worsening | 0.17 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Oedema: Worsening related to study drug | 0.08 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Epistaxis: Improvement | 0.02 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Epistaxis: Worsening | 0.02 proportion of nostril assessments |
| Intranasal Fentanyl Spray (INFS) | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score | Epistaxis: Worsening related to study drug | 0.02 proportion of nostril assessments |
Secondary
Number of Participants With Adverse Events (AEs)
The severity (intensity of each AE was assessed as mild (transient symptoms, no interference with daily activities), moderate (marked symptoms, moderate interference with daily activities), or severe (considerable interference with daily activities) by the investigator. Serious adverse events are defined as any untoward medical occurrence that at any dose results in death or is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect. The investigator assessed each AE as either related or not related to study treatment.
Time frame: 12 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | Any AE | 23 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | Non-serious adverse events | 22 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | Serious adverse events | 2 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | AEs with an onset within 30 minutes of first dose | 11 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | AEs leading to withdrawal | 2 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | Deaths | 2 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | AEs possibly associated with nasal intolerability | 2 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | Any AE reported as related to treatment | 14 participants |
| Intranasal Fentanyl Spray (INFS) | Number of Participants With Adverse Events (AEs) | Severe adverse events | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Non-serious adverse events | 5 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE reported as related to treatment | 4 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | AEs leading to withdrawal | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | AEs possibly associated with nasal intolerability | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | AEs with an onset within 30 minutes of first dose | 3 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Severe adverse events | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any AE | 6 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Serious adverse events | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Deaths | 1 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | Serious adverse events | 8 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | Any AE | 22 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | Any AE reported as related to treatment | 6 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | Non-serious adverse events | 17 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | AEs with an onset within 30 minutes of first dose | 5 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | Deaths | 5 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | Severe adverse events | 7 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | AEs leading to withdrawal | 3 participants |
| Tolerability Phase | Number of Participants With Adverse Events (AEs) | AEs possibly associated with nasal intolerability | 6 participants |