NOSE-400: A Clinical Trial With Intranasal Fentanyl in Cancer Patients With Breakthrough Pain
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: Intranasal 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.
Other Names:
Drug: Placebo
Matching intranasal placebo spray
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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: 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".
- 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".
- 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.
Eligibility Criteria
Criteria
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:
-
Has the patient had an illicit substance abuse within the last year prior to screening?
-
Does the patient have severe hepatic impairment? - defined as alanine aminotransferase (ALT or) aspartate aminotransferase (AST) levels > 3x upper limit of normal (ULN)
-
Does the patient have severe renal impairment? - defined as serum creatinine ≥ 3.0 mg/dl (265 micromol/L)
-
Has the patient ever had facial radiotherapy or is the patient scheduled to facial radiotherapy?
-
Has the patient been treated with any monoamine oxidase (MAO) inhibitors within the last 14 days prior to the screening visit?
-
Does the patient have severe impaired respiratory function, which may increase the risk of clinically relevant respiratory depression by BTP fentanyl treatment?
-
Is the patient known to be hypersensitive to fentanyl or to other opioids or any of their excipients?
-
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?
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Budapest | Hungary | |||
| 2 | Debrecen | Hungary | |||
| 3 | Kazincbarcika | Hungary | |||
| 4 | Nyíregyháza | Hungary | |||
| 5 | Pécs | Hungary | |||
| 6 | Drammen | Norway | |||
| 7 | Trondheim | Norway | |||
| 8 | Moscow | Russian Federation | |||
| 9 | Smolensk | Russian Federation | |||
| 10 | St. Petersburg | Russian Federation | |||
| 11 | Yaroslavl | Russian Federation |
Sponsors and Collaborators
- Takeda
Investigators
- Study Director: Medical Director, Clinical Science, Takeda
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- FT-1301-032-SP
- 2010-021096-85
- U1111-1133-6364
- 2011/776
Study Results
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 Detail | 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. |
| Arm/Group Title | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Arm/Group Description | 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. |
| Period Title: Titration Phase | |
| STARTED | 45 |
| COMPLETED | 33 |
| NOT COMPLETED | 12 |
| Period Title: Titration Phase | |
| STARTED | 15 |
| COMPLETED | 13 |
| NOT COMPLETED | 2 |
| Period Title: Titration Phase | |
| STARTED | 31 |
| COMPLETED | 16 |
| NOT COMPLETED | 15 |
Baseline Characteristics
| Arm/Group Title | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 46 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
61.0
(9.09)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
31
67.4%
|
| Male |
15
32.6%
|
| Race/Ethnicity, Customized (participants) [Number] | |
| White |
46
100%
|
| Region of Enrollment (participants) [Number] | |
| Hungary |
33
71.7%
|
| Norway |
10
21.7%
|
| Russian Federation |
3
6.5%
|
| Site of Primary Tumour Reported in >5% Patients (participants) [Number] | |
| Breast |
14
30.4%
|
| Lung respiratory system |
5
10.9%
|
| Gastro-oesophageal |
1
2.2%
|
| Colon/rectal |
3
6.5%
|
| Pancreas |
6
13%
|
| Female genital |
3
6.5%
|
| Prostate |
3
6.5%
|
| Urological |
7
15.2%
|
| Unknown Primary Tumour |
2
4.3%
|
| Liver |
1
2.2%
|
| Other |
1
2.2%
|
Outcome Measures
| Title | Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Arm/Group Description | In the Efficacy phase participants received 400 μg INFS for 6 episodes of breakthrough pain. | In the Efficacy Phase Participants received placebo intranasal spray for 2 episodes of breakthrough pain. |
| Measure Participants | 15 | 15 |
| Least Squares Mean (95% Confidence Interval) [units on a scale] |
2.5
|
1.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Intranasal Fentanyl Spray (INFS), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.002 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | A mixed effects model with episode baseline PI as a covariate, treatment as a fixed effect and patient as a random effect. | |
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | 1.1 | |
| Confidence Interval |
(2-Sided) 95% 0.41 to 1.179 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 46 |
| Measure Nostrils | 54 |
| Change of color: Improvement |
0.06
|
| Change of color: Worsening |
0.09
|
| Change of color: Worsening related to study drug |
0.09
|
| Inflammation: Improvement |
0.04
|
| Inflammation: Worsening |
0.07
|
| Inflammation: Worsening related to study drug |
0.07
|
| Sore nose: Improvement |
0.04
|
| Sore nose: Worsening |
0.04
|
| Sore nose: Worsening related to study drug |
0.04
|
| Ulceration: Improvement |
NA
|
| Ulceration: Worsening |
0.04
|
| Ulceration: Worsening related to study drug |
0.04
|
| Dry nose: Improvement |
0.09
|
| Dry nose: Worsening |
0.06
|
| Dry nose: Worsening related to study drug |
NA
|
| Runny nose: Improvement |
0.04
|
| Runny nose: Worsening |
0.13
|
| Runny nose: Worsening related to study drug |
0.10
|
| Stuffed nose: Improvement |
0.06
|
| Stuffed nose: Worsening |
0.17
|
| Stuffed nose: Worsening related to study drug |
0.08
|
| Oedema: Improvement |
0.04
|
| Oedema: Worsening |
0.17
|
| Oedema: Worsening related to study drug |
0.08
|
| Epistaxis: Improvement |
0.02
|
| Epistaxis: Worsening |
0.02
|
| Epistaxis: Worsening related to study drug |
0.02
|
| Title | Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy Phase, Full Analysis Set |
| Arm/Group Title | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Arm/Group Description | In the Efficacy phase participants received 400 μg INFS for 6 episodes of breakthrough pain. | In the Efficacy Phase Participants received placebo intranasal spray for 2 episodes of breakthrough pain. |
| Measure Participants | 15 | 15 |
| PID at 5 minutes |
1.3
|
0.8
|
| PID at 30 minutes |
3.0
|
1.8
|
| PID at 60 minutes |
3.3
|
2.2
|
| Title | Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy Phase, Full Analysis Set |
| Arm/Group Title | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Arm/Group Description | In the Efficacy phase participants received 400 μg INFS for 6 episodes of breakthrough pain. | In the Efficacy Phase Participants received placebo intranasal spray for 2 episodes of breakthrough pain. |
| Measure Participants | 15 | 15 |
| SPID30 |
0.6
|
0.4
|
| SPID60 |
0.7
|
0.5
|
| Title | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy Phase, Full Analysis Set |
| Arm/Group Title | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Arm/Group Description | In the Efficacy phase participants received 400 μg INFS for 6 episodes of breakthrough pain. | In the Efficacy Phase Participants received placebo intranasal spray for 2 episodes of breakthrough pain. |
| Measure Participants | 15 | 15 |
| Measure breakthrough pain episodes | 88 | 29 |
| ≥ 1 point reduction in PI at 5 minutes |
0.61
|
0.45
|
| ≥ 1 point reduction in PI at 10 minutes |
0.74
|
0.55
|
| ≥ 1 point reduction in PI at 30 minutes |
0.81
|
0.66
|
| ≥ 1 point reduction in PI at 60 minutes |
0.86
|
0.69
|
| ≥ 2 point reduction in PI at 5 minutes |
0.33
|
0.24
|
| ≥ 2 point reduction in PI at 10 minutes |
0.51
|
0.31
|
| ≥ 2 point reduction in PI at 30 minutes |
0.60
|
0.41
|
| ≥ 2 point reduction in PI at 60 minutes |
0.65
|
0.48
|
| ≥ 3 point reduction in PI at 5 minutes |
0.18
|
0.17
|
| ≥ 3 point reduction in PI at 10 minutes |
0.32
|
0.24
|
| ≥ 3 point reduction in PI at 30 minutes |
0.45
|
0.34
|
| ≥ 3 point reduction in PI at 60 minutes |
0.50
|
0.48
|
| Title | Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy Phase, Full Analysis Set |
| Arm/Group Title | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Arm/Group Description | In the Efficacy phase participants received 400 μg INFS for 6 episodes of breakthrough pain. | In the Efficacy Phase Participants received placebo intranasal spray for 2 episodes of breakthrough pain. |
| Measure Participants | 15 | 15 |
| Measure breakthrough pain episodes | 88 | 29 |
| > 33% reduction in PI at 5 minutes |
0.23
|
0.17
|
| > 33% reduction in PI at 10 minutes |
0.44
|
0.24
|
| > 33% reduction in PI at 30 minutes |
0.55
|
0.34
|
| > 33% reduction in PI at 60 minutes |
0.58
|
0.48
|
| ≥ 50% reduction in PI at 5 minutes |
0.11
|
0.07
|
| ≥ 50% reduction in PI at 10 minutes |
0.31
|
0.21
|
| ≥ 50% reduction in PI at 30 minutes |
0.49
|
0.31
|
| ≥ 50% reduction in PI at 60 minutes |
0.52
|
0.34
|
| Title | Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy Phase, Full Analysis Set |
| Arm/Group Title | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Arm/Group Description | In the Efficacy phase participants received 400 μg INFS for 6 episodes of breakthrough pain. | In the Efficacy Phase Participants received placebo intranasal spray for 2 episodes of breakthrough pain. |
| Measure Participants | 15 | 15 |
| Least Squares Mean (95% Confidence Interval) [units on a scale] |
1.9
|
1.1
|
| Title | Number of Participants With Adverse Events (AEs) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set |
| Arm/Group Title | Titration Phase | Efficacy Phase | Tolerability Phase |
|---|---|---|---|
| Arm/Group Description | All participants were step-wise titrated to an effective dose of 50, 100, 200 or 400 μg INFS in the Titration Phase. | 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. |
| Measure Participants | 45 | 15 | 31 |
| Any AE |
23
50%
|
6
NaN
|
22
NaN
|
| Any AE reported as related to treatment |
14
30.4%
|
4
NaN
|
6
NaN
|
| Non-serious adverse events |
22
47.8%
|
5
NaN
|
17
NaN
|
| Serious adverse events |
2
4.3%
|
2
NaN
|
8
NaN
|
| Deaths |
2
4.3%
|
1
NaN
|
5
NaN
|
| Severe adverse events |
2
4.3%
|
2
NaN
|
7
NaN
|
| AEs leading to withdrawal |
2
4.3%
|
2
NaN
|
3
NaN
|
| AEs possibly associated with nasal intolerability |
2
4.3%
|
0
NaN
|
6
NaN
|
| AEs with an onset within 30 minutes of first dose |
11
23.9%
|
3
NaN
|
5
NaN
|
Adverse Events
| Time Frame | 12 weeks | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. | |||||
| Arm/Group Title | Titration Phase | Efficacy Phase | Tolerability Phase | |||
| Arm/Group Description | 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. | |||
All Cause Mortality |
||||||
| Titration Phase | Efficacy Phase | Tolerability Phase | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Titration Phase | Efficacy Phase | Tolerability Phase | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/45 (4.4%) | 2/15 (13.3%) | 8/31 (25.8%) | |||
| Cardiac disorders | ||||||
| Cardiovascular insufficiency | 0/45 (0%) | 1/15 (6.7%) | 0/31 (0%) | |||
| General disorders | ||||||
| Device occlusion | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Disease progression | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Hepatobiliary disorders | ||||||
| Jaundice | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Femur fracture | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Malignant neoplasm progression | 1/45 (2.2%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Metastases to lung | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Psychiatric disorders | ||||||
| Depression | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Renal and urinary disorders | ||||||
| Azotaemia | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Respiratory depression | 0/45 (0%) | 1/15 (6.7%) | 1/31 (3.2%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Titration Phase | Efficacy Phase | Tolerability Phase | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 22/45 (48.9%) | 5/15 (33.3%) | 17/31 (54.8%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 0/45 (0%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Cardiac disorders | ||||||
| Tachycardia | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Vertigo | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal discomfort | 0/45 (0%) | 1/15 (6.7%) | 0/31 (0%) | |||
| Abdominal hernia | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Abdominal pain upper | 1/45 (2.2%) | 1/15 (6.7%) | 2/31 (6.5%) | |||
| Constipation | 1/45 (2.2%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Diarrhoea | 3/45 (6.7%) | 0/15 (0%) | 0/31 (0%) | |||
| Dry mouth | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Nausea | 10/45 (22.2%) | 1/15 (6.7%) | 8/31 (25.8%) | |||
| Vomiting | 3/45 (6.7%) | 1/15 (6.7%) | 4/31 (12.9%) | |||
| General disorders | ||||||
| Asthenia | 1/45 (2.2%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Discomfort | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Face oedema | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Fatigue | 3/45 (6.7%) | 1/15 (6.7%) | 1/31 (3.2%) | |||
| General physical health deterioration | 2/45 (4.4%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Irritability | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Pyrexia | 1/45 (2.2%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Infections and infestations | ||||||
| Bronchitis | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Influenza | 1/45 (2.2%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Nasopharyngitis | 0/45 (0%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Injury, poisoning and procedural complications | ||||||
| Procedural dizziness | 0/45 (0%) | 1/15 (6.7%) | 0/31 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Cachexia | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Decreased appetite | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Dehydration | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Joint stiffness | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Joint swelling | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Muscle rigidity | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Musculoskeletal pain | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Osteoarthritis | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Malignant neoplasm progression | 0/45 (0%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Nervous system disorders | ||||||
| Dizziness | 8/45 (17.8%) | 2/15 (13.3%) | 4/31 (12.9%) | |||
| Headache | 1/45 (2.2%) | 0/15 (0%) | 3/31 (9.7%) | |||
| Horner's syndrome | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Hypoaesthesia | 0/45 (0%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Paraesthesia | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Sedation | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Somnolence | 2/45 (4.4%) | 0/15 (0%) | 0/31 (0%) | |||
| Tremor | 1/45 (2.2%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Psychiatric disorders | ||||||
| Anxiety | 0/45 (0%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Emotional distress | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Insomnia | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Sleep disorder | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Renal and urinary disorders | ||||||
| Dysuria | 1/45 (2.2%) | 0/15 (0%) | 0/31 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Dry throat | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Dyspnoea | 0/45 (0%) | 0/15 (0%) | 2/31 (6.5%) | |||
| Epistaxis | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Hiccups | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Nasal congestion | 1/45 (2.2%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Nasal discomfort | 1/45 (2.2%) | 0/15 (0%) | 3/31 (9.7%) | |||
| Nasal dryness | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Nasal oedema | 0/45 (0%) | 0/15 (0%) | 3/31 (9.7%) | |||
| Nasal ulcer | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Hyperhidrosis | 2/45 (4.4%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Pruritus | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Urticaria | 0/45 (0%) | 1/15 (6.7%) | 0/31 (0%) | |||
| Vascular disorders | ||||||
| Hot flush | 1/45 (2.2%) | 0/15 (0%) | 1/31 (3.2%) | |||
| Superior vena cava syndrome | 0/45 (0%) | 0/15 (0%) | 1/31 (3.2%) | |||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
| Name/Title | Medical Director |
|---|---|
| Organization | Takeda |
| Phone | +1-800-778-2860 |
| clinicaltrialregistry@tpna.com |
- FT-1301-032-SP
- 2010-021096-85
- U1111-1133-6364
- 2011/776