A Clinical Trial With Intranasal Fentanyl in Cancer Patients With Breakthrough Pain (NOSE-400)

Study Description

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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
Break Through Pain; Cancer	Drug: Intranasal Fentanyl Spray (INFS); Drug: Placebo	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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	46 participants
Intervention Model:	Single Group Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	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.
Study Start Date :	August 2011
Actual Primary Completion Date :	January 2013
Actual Study Completion Date :	January 2013

Arms and Interventions

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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 Name: Instanyl®; Drug: Placebo; Matching intranasal placebo spray

Outcome Measures

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Primary Outcome Measures :

1. Induction Phase: Pain Intensity Difference at 10 Minutes (PID10) After Treatment [ Time Frame: 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 :

1. Incidence of Improvement or Worsening in Nasal Mucosa Sign or Abnormality Score [ Time Frame: 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
2. Efficacy Phase: Pain Intensity Difference (PID) at 5, 30, and 60 Minutes After First Dose of Study Drug [ Time Frame: 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.
3. Efficacy Phase: Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) Derived From PI Scores [ Time Frame: 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.

4. Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 1, 2 or 3 Point Reduction in Pain Intensity [ Time Frame: 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".
5. Efficacy Phase: Proportion of BTP Episodes With a Positive Response Defined as a ≥ 33% or 50% Reduction in Pain Intensity [ Time Frame: 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".
6. Efficacy Phase: General Impression (GI) Score at 60 Minutes After First Dose [ Time Frame: 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.
7. Number of Participants With Adverse Events (AEs) [ Time Frame: 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

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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:

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?

Contacts and Locations

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Locations

Hungary
Budapest, Hungary
Debrecen, Hungary
Kazincbarcika, Hungary
Nyíregyháza, Hungary
Pécs, Hungary
Norway
Drammen, Norway
Trondheim, Norway
Russian Federation
Moscow, Russian Federation
Smolensk, Russian Federation
St. Petersburg, Russian Federation
Yaroslavl, Russian Federation

Sponsors and Collaborators

Takeda

Investigators

Study Director:	Medical Director, Clinical Science	Takeda

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Thronæs M, Popper L, Eeg M, Jaatun E, Kvitberg M, Kaasa S. Efficacy and tolerability of intranasal fentanyl spray in cancer patients with breakthrough pain. Clin Ther. 2015 Mar 1;37(3):585-96. doi: 10.1016/j.clinthera.2014.12.010. Epub 2015 Jan 30.

Responsible Party:	Takeda
ClinicalTrials.gov Identifier:	NCT01429051 History of Changes
Other Study ID Numbers:	FT-1301-032-SP; 2010-021096-85 ( EudraCT Number ); U1111-1133-6364 ( Registry Identifier: WHO ); 2011/776 ( Registry Identifier: REK )
First Posted:	September 5, 2011
Results First Posted:	March 26, 2014
Last Update Posted:	March 26, 2014
Last Verified:	February 2014

Keywords provided by Takeda:

Break through pain; BTP; Cancer	Intranasal Fentanyl Spray; INFS; cancer patients

Additional relevant MeSH terms:

Breakthrough Pain; Pain; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Fentanyl; Analgesics, Opioid; Narcotics; Central Nervous System Depressants	Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adjuvants, Anesthesia; Anesthetics, Intravenous; Anesthetics, General; Anesthetics