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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 Evaluat

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 Summary: 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.
Sponsor: Takeda

Current Primary Outcome: 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. ]

Original Primary Outcome: Pain intensity difference at 10 minutes (PID10) after treatment with 400µg INFS [ Time Frame: During the efficacy phase (II) [= treatment of 8 BTP episodes] ]

Current Secondary Outcome:

• 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
• 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.
• 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.

• 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".
• 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".
• 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.




Original Secondary Outcome:

• Nasal tolerability of INFS after 12 weeks treatment [ Time Frame: Baseline prior to IMP treatment and at 12 weeks ]

  The change from baseline assessment of each nasal mucosa sign will be rated by the oto-rhino-laryngologist as either related or not related to the use of IMP, 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

  The changes in the scores will be presented as:

  • No change (score at baseline and week 12 equal)
  • Improvement from baseline (score at baseline highest)
  • Worsening from baseline (score at week 12 highest)
• Pain intensity difference (PID) at 5, 30, and 60 minutes after first dose of IMP [ Time Frame: During the efficacy phase (II) [= treatment of 8 BTP episodes] ]

  During the efficacy phase patients must assess their pain intensity of each of the investigational medicinal product (IMP) treated breakthrough pain (BTP) episode at 5, 30 and 60 minutes after first dose of IMP; using the 11-point Numerical Rating Scale (NRS) from 0 to 10, where 0 represents the absence of pain and 10 is "worst possible pain".

  PID5, PID30 and PID60 is calculated as the difference in pain intensity from time 0 to 5 minutes PID5, time 0 to 30 minutes PID30 and time 0 to 60 minutes PID60. A positive value is a decrease (improvement) of the pain.

• Sum of Pain Intensity Differences (SPID0-60 and SPID0-30) derived from PI scores [ Time Frame: During 12 weeks treatment ]
  SPID0-60 and SPID0-30 is calculated as the sum of difference in pain intensity from time 0 to 60 minutes SPID60 and from time 0 to 30 minutes SPID30. A positive value is a decrease (improvement) of the pain.
• Responder rates of pain intensity at all time points (PIt) [ Time Frame: During the efficacy phase (II) [= treatment of 8 BTP episodes] ]
  Overall responder rate is defined as the percentage of BTP episodes with a positive response to treatment (INFS or placebo). The following definitions of a positive response will be analysed: greater than 33 percent reduction in PIt, greater than or equal to 50 percent reduction in PIt, greater than or equal to 1 reduction in PIt, greater than or equal to 2 reduction in PIt, and greater than or equal to 3 reduction in PIt.
• General Impression (GI) at 60 minutes after first dose of IMP [ Time Frame: During 12 weeks treatment ]

  During all treatment phases, the patients must assess their general impression (GI) of treatment efficacy for an IMP treated BTP episode 1 hour (at 60 minutes) after first dose of IMP.

  The validated, categorical 5-point score Verbal Rating Scale (VRS), will be used for this assessment and scored as follows:

  • 0 =poor
  • 1 =fair
  • 2 =good
  • 3 =very good
  • 4 =excellent

  All evaluations must be assessed by the patient, and recorded in the patient diary.

• Safety profile of treatment with all dose strengths between 50 μg and 400 μg [ Time Frame: During 12 weeks treatment ]
  Adverse Events


Information By: Takeda


Dates:
Date Received: September 1, 2011
Date Started: August 2011
Date Completion:
Last Updated: February 20, 2014
Last Verified: February 2014