Symptoms and General Pathology

All Conditions

Nervous System Diseases

Rare Diseases

Pain

Breakthrough Pain

Neurologic Manifestations

Oculocerebral Syndrome With Hypopigmentation

Adjuvants, Anesthesia

Analgesics

Central Nervous System Depressants

All Drugs and Chemicals

Hematinics

Fentanyl

Iron-Dextran Complex

Analgesics, Opioid

Narcotics

Anesthetics

Anesthetics, Intravenous

Anesthetics, General

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.

Applied as 1 puff (= 1 dose) in one nostril, or applied as two puffs (= 2 doses, 1 in each nostril) with ten minutes apart.

Intranasal Fentanyl Spray (INFS)

Placebo

Medical Director, Clinical Science

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.

A Clinical Trial With Intranasal Fentanyl in Cancer Patients With Breakthrough Pain

A Dose Titrated Clinical Trial With a Placebo-controlled, Double-blind, Randomised, Cross-over Phase to Demonstrate the Efficacy of 400 μg Intranasal Fentanyl (INFS) Dose Strength, and to Evaluate 12 Weeks Safety and Nasal Tolerability of All Dose Strengths Between 50 μg and 400 μg, in Cancer Patients With Breakthrough Pain.

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.

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

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.

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.

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".

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".

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.

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.

Takeda

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.

Participants were step-wise titrated to an effective dose of 50, 100, 200 or 400 μg INFS in the Titration Phase (I).

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.

Efficacy Phase

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.

Tolerability Phase

Age, Continuous

Sex: Female, Male

White

Race/Ethnicity, Customized

Hungary

Norway

Russian Federation

Region of Enrollment

Breast

Lung respiratory system

Gastro-oesophageal

Colon/rectal

Pancreas

Female genital

Prostate

Urological

Unknown Primary Tumour

Liver

Other

Site of Primary Tumour Reported in >5% Patients

The safety analysis set included all participants who received at least 1 dose of INFS (including the initial test dose).

Medical Director

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.

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.

Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment

Change of color: Improvement

Change of color: Worsening

Change of color: Worsening related to study drug

Inflammation: Improvement

Inflammation: Worsening

Inflammation: Worsening related to study drug

Sore nose: Improvement

Sore nose: Worsening

Sore nose: Worsening related to study drug

Ulceration: Improvement

Ulceration: Worsening

Ulceration: Worsening related to study drug

Dry nose: Improvement

Dry nose: Worsening

Dry nose: Worsening related to study drug

Runny nose: Improvement

Runny nose: Worsening

Runny nose: Worsening related to study drug

Stuffed nose: Improvement

Stuffed nose: Worsening

Stuffed nose: Worsening related to study drug

Oedema: Improvement

Oedema: Worsening

Oedema: Worsening related to study drug

Epistaxis: Improvement

Epistaxis: Worsening

Epistaxis: Worsening related to study drug

Safety Analysis Set, which included all patients who received at least 1 dose of INFS (including the initial test dose) with non-missing assessments.

Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score

PID at 5 minutes

PID at 30 minutes

PID at 60 minutes

Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug

SPID30

SPID60

Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores

≥ 1 point reduction in PI at 5 minutes

≥ 1 point reduction in PI at 10 minutes

≥ 1 point reduction in PI at 30 minutes

≥ 1 point reduction in PI at 60 minutes

≥ 2 point reduction in PI at 5 minutes

≥ 2 point reduction in PI at 10 minutes

≥ 2 point reduction in PI at 30 minutes

≥ 2 point reduction in PI at 60 minutes

≥ 3 point reduction in PI at 5 minutes

≥ 3 point reduction in PI at 10 minutes

≥ 3 point reduction in PI at 30 minutes

≥ 3 point reduction in PI at 60 minutes

Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity

> 33% reduction in PI at 5 minutes

> 33% reduction in PI at 10 minutes

> 33% reduction in PI at 30 minutes

> 33% reduction in PI at 60 minutes

≥ 50% reduction in PI at 5 minutes

≥ 50% reduction in PI at 10 minutes

≥ 50% reduction in PI at 30 minutes

≥ 50% reduction in PI at 60 minutes

Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity

Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose

Any AE

Any AE reported as related to treatment

Non-serious adverse events

Serious adverse events

Deaths

Severe adverse events

AEs leading to withdrawal

AEs possibly associated with nasal intolerability

AEs with an onset within 30 minutes of first dose

All participants were step-wise titrated to an effective dose of 50, 100, 200 or 400 μg INFS in the Titration Phase.

Number of Participants With Adverse Events (AEs)

Anticoagulants

Other Dietary Supplements

Citric Acid

Sodium Citrate

Citrate

ACTIQ (Oral transmucosal fentanyl citrate)

The primary objective of the study is to determine whether a test titration regimen of ACTIQ treatment will reduce the number of inadequately managed episodes of breakthrough pain for an individual patient by attaining a successful dose of ACTIQ treatment more quickly. The successful ACTIQ dose provides a satisfactory combination of efficacy and tolerability after a single administration, as assessed by the patient.

Evaluate the Efficacy and Safety of ACTIQ in Patients With Cancer and Breakthrough Pain

A Randomised, Open-label, Parallel-group Study to Evaluate the Efficacy and Safety of ACTIQ (Oral Transmucosal Fentanyl Citrate) Titrated According to 2 Regimens in Patients With Cancer and Breakthrough Pain

Cephalon

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Clinical Trial With Intranasal Fentanyl in Cancer Patients With Breakthrough Pain	NCT01429051	Break Through P... Cancer	Intranasal Fent... Placebo	18 Years -	Takeda
Evaluate the Efficacy and Safety of ACTIQ in Patients With Cancer and Breakthrough Pain	NCT00236145	Breakthrough Pa...	ACTIQ (Oral tra...	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.
Evaluate the Efficacy and Safety of ACTIQ in Patients With Cancer and Breakthrough Pain	NCT00236145	Breakthrough Pa...	ACTIQ (Oral tra...	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.

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