A Phase 3 interventional study of Intranasal Fentanyl Spray (INFS) and Placebo in Break Through Pain and Cancer, sponsored by Takeda. Completed at 11 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-03-26.
Sponsored by Takeda · Phase 3, Interventional, and Treatment
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.
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.
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All inclusion criteria were answered 'yes' for a patient to participate in the clinical trial.
Exclusion Criteria:
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) · Drug: Placebo
Applied as 1 puff (= 1 dose) in one nostril, or applied as two puffs (= 2 doses, 1 in each nostril) with ten minutes apart.
Also known as: Instanyl®
Matching intranasal placebo spray
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.
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
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.
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
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
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
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.
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
Participants took part in the study at 11 investigative sites in Hungary, Norway and Russia from 08 August 2011 to 04 January 2013.
| Milestone | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Started | 45 |
| Completed | 33 |
| Not completed | 12 |
| Withdrew: Death | 1 |
| Withdrew: Withdrawal by subject | 7 |
| Withdrew: Physician decision | 1 |
| Withdrew: Unsuccessful titration at any dose | 1 |
| Withdrew: Less than 3 btp episodes per week | 2 |
| Milestone | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Started | 15 |
| Completed | 13 |
| Not completed | 2 |
| Withdrew: Adverse event | 1 |
| Withdrew: Death | 1 |
| Milestone | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Started | 31 |
| Completed | 16 |
| Not completed | 15 |
| Withdrew: Death | 5 |
| Withdrew: Adverse event | 2 |
| Withdrew: Withdrawal by subject | 5 |
| Withdrew: Physician decision | 1 |
| Withdrew: Other | 2 |
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.
| units on a scale | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment | 2.5 (1.42 to 3.49) | 1.4 (0.23 to 2.48) |
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
| proportion of nostril assessments | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Change of color: Improvement | 0.06 (0.00 to 0.12) |
| Change of color: Worsening | 0.09 (0.02 to 0.17) |
| Change of color: Worsening related to study drug | 0.09 (0.02 to 0.17) |
| Inflammation: Improvement | 0.04 (0.00 to 0.09) |
| Inflammation: Worsening | 0.07 (0.00 to 0.14) |
| Inflammation: Worsening related to study drug | 0.07 (0.00 to 0.14) |
| Sore nose: Improvement | 0.04 (0.00 to 0.09) |
| Sore nose: Worsening | 0.04 (0.00 to 0.09) |
| Sore nose: Worsening related to study drug | 0.04 (0.00 to 0.09) |
| Ulceration: Improvement | NA (NA to NA) |
| Ulceration: Worsening | 0.04 (0.00 to 0.09) |
| Ulceration: Worsening related to study drug | 0.04 (0.00 to 0.09) |
| Dry nose: Improvement | 0.09 (0.02 to 0.17) |
| Dry nose: Worsening | 0.06 (0.00 to 0.12) |
| Dry nose: Worsening related to study drug | NA (NA to NA) |
| Runny nose: Improvement | 0.04 (0.00 to 0.09) |
| Runny nose: Worsening | 0.13 (0.04 to 0.22) |
| Runny nose: Worsening related to study drug | 0.10 (0.02 to 0.18) |
| Stuffed nose: Improvement | 0.06 (0.00 to 0.12) |
| Stuffed nose: Worsening | 0.17 (0.07 to 0.27) |
| Stuffed nose: Worsening related to study drug | 0.08 (0.00 to 0.15) |
| Oedema: Improvement | 0.04 (0.00 to 0.09) |
| Oedema: Worsening | 0.17 (0.07 to 0.27) |
| Oedema: Worsening related to study drug | 0.08 (0.00 to 0.15) |
| Epistaxis: Improvement | 0.02 (0.00 to 0.05) |
| Epistaxis: Worsening | 0.02 (0.00 to 0.05) |
| Epistaxis: Worsening related to study drug | 0.02 (0.00 to 0.05) |
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.
| units on a scale | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| PID at 5 minutes | 1.3 (0.72 to 1.89) | 0.8 (0.18 to 1.51) |
| PID at 30 minutes | 3.0 (2.03 to 3.88) | 1.8 (0.79 to 2.88) |
| PID at 60 minutes | 3.3 (2.34 to 4.17) | 2.2 (1.17 to 3.27) |
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.
| units on a scale | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| SPID30 | 0.6 (0.38 to 0.90) | 0.4 (0.09 to 0.67) |
| SPID60 | 0.7 (0.46 to 1.04) | 0.5 (0.13 to 0.77) |
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".
| proportion of breakthrough pain episodes | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| ≥ 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 |
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".
| proportion of breakthrough pain episodes | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| > 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 |
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.
| units on a scale | Intranasal Fentanyl Spray (INFS) | Placebo |
|---|---|---|
| Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose | 1.9 (1.41 to 2.47) | 1.1 (0.52 to 1.71) |
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.
| participants | Titration Phase | Efficacy Phase | Tolerability Phase |
|---|---|---|---|
| Any AE | 23 | 6 | 22 |
| Any AE reported as related to treatment | 14 | 4 | 6 |
| Non-serious adverse events | 22 | 5 | 17 |
| Serious adverse events | 2 | 2 | 8 |
| Deaths | 2 | 1 | 5 |
| Severe adverse events | 2 | 2 | 7 |
| AEs leading to withdrawal | 2 | 2 | 3 |
| AEs possibly associated with nasal intolerability | 2 | 0 | 6 |
| AEs with an onset within 30 minutes of first dose | 11 | 3 | 5 |
Collected over 12 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Titration Phase | — | 2/45 (4.4%) | 22/45 (48.9%) |
| Efficacy Phase | — | 2/15 (13.3%) | 5/15 (33.3%) |
| Tolerability Phase | — | 8/31 (25.8%) | 17/31 (54.8%) |
| Event | Titration Phase | Efficacy Phase | Tolerability Phase |
|---|---|---|---|
| Cardiovascular insufficiencyCardiac disorders | 0/45 | 1/15 | 0/31 |
| Respiratory depressionRespiratory, thoracic and mediastinal disorders | 0/45 | 1/15 | 1/31 |
| Malignant neoplasm progressionNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/45 | 0/15 | 2/31 |
| Device occlusionGeneral disorders | 0/45 | 0/15 | 1/31 |
| Disease progressionGeneral disorders | 0/45 | 0/15 | 1/31 |
| Femur fractureInjury, poisoning and procedural complications | 0/45 | 0/15 | 1/31 |
| Metastases to lungNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/45 | 0/15 | 1/31 |
| DepressionPsychiatric disorders | 0/45 | 0/15 | 1/31 |
| AzotaemiaRenal and urinary disorders | 0/45 | 0/15 | 1/31 |
| JaundiceHepatobiliary disorders | 1/45 | 0/15 | 0/31 |
| Event | Titration Phase | Efficacy Phase | Tolerability Phase |
|---|---|---|---|
| NauseaGastrointestinal disorders | 10/45 | 1/15 | 8/31 |
| DizzinessNervous system disorders | 8/45 | 2/15 | 4/31 |
| VomitingGastrointestinal disorders | 3/45 | 1/15 | 4/31 |
| HeadacheNervous system disorders | 1/45 | 0/15 | 3/31 |
| Nasal discomfortRespiratory, thoracic and mediastinal disorders | 1/45 | 0/15 | 3/31 |
| Nasal oedemaRespiratory, thoracic and mediastinal disorders | 0/45 | 0/15 | 3/31 |
| Abdominal discomfortGastrointestinal disorders | 0/45 | 1/15 | 0/31 |
| Abdominal pain upperGastrointestinal disorders | 1/45 | 1/15 | 2/31 |
| DiarrhoeaGastrointestinal disorders | 3/45 | 0/15 | 0/31 |
| FatigueGeneral disorders | 3/45 | 1/15 | 1/31 |
The safety analysis set included all participants who received at least 1 dose of INFS (including the initial test dose).
| Age, Continuous(years) | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Mean | 61.0 ± 9.09 |
| Sex: Female, Male(Participants) | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Female | 31 |
| Male | 15 |
| Race/Ethnicity, Customized(participants) | Intranasal Fentanyl Spray (INFS) |
|---|---|
| White | 46 |
| Region of Enrollment(participants) | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Hungary | 33 |
| Norway | 10 |
| Russian Federation | 3 |
| Site of Primary Tumour Reported in >5% Patients(participants) | Intranasal Fentanyl Spray (INFS) |
|---|---|
| Breast | 14 |
| Lung respiratory system | 5 |
| Gastro-oesophageal | 1 |
| Colon/rectal | 3 |
| Pancreas | 6 |
| Female genital | 3 |
| Prostate | 3 |
| Urological | 7 |
| Unknown Primary Tumour | 2 |
| Liver | 1 |
| Other | 1 |
The record gives a start of Aug 2011, a primary completion of Jan 2013 and a completion of Jan 2013. It does not say whether these dates are actual or estimated.
Results were first posted in Mar 2014, 1 year 2 months after primary completion.
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Studies of the drug tested here: Fentanyl Citrate-containing Nasal Spray