Effectiveness and Tolerance of Inhaled Fentanyl Aerosol (25µg/Dose) in Chinese Patients With Breakthrough Cancer Pain

Study Overview
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Brief Summary
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Breakthrough cancer pain (BTcP) is a common problem in patients with cancer. This is a phase I/IIa, pharmacokinetic, dose-response and safety study of inhaled fentanyl aerosol (25µg/dose) in Chinese patients with breakthrough cancer pain. The study will include two stages.

Detailed Description
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Stage I: dose-response relationship and safety assessment of inhaled fentanyl aerosol in patients with breakthrough cancer pain. placebo-controlled, cross-over, double-blind randomized design is applied in this stage. Patients meeting the inclusion/exclusion criteria will be treated with inhaled fentanyl aerosol (4 of 6 episodes BTcp) or placebo (2of 6 episodes BTcp).Subjects will inhale fentanyl aerosol or placebo for each episode of BTcp with a starting dose of 25 µg every 4 minutes until adequate pain alleviation. The maximum doses are 6×25 µg. Stage II: The dosage regimen (number of puffs) will be depended on the data from Stage I. Subjects will inhale fentanyl aerosol not in the episode of breakthrough cancer pain with a starting dose of 25 µg every 4 minutes.

Official Title
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A Phase I/IIa, Pharmacokinetic, Dose-response and Safety Study of Inhaled Fentanyl Aerosol (25µg/Dose) in Chinese Patients With Breakthrough Cancer Pain

Conditions
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Breakthrough Cancer Pain

Intervention / Treatment
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* Drug: Inhaled fentanyl aerosol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 to 75years, inclusive. Subjects must be diagnosed with cancer. Subjects must be opioid-tolerant : taking oral morphine more than 60mg and less than 1000mg,or taking other equivalent potency opioids of analgesic doses in one weeks or longer. Subjects must experience persistent pain associated with cancer, and the pain score assessed by NRS should be <4 within 24hour before screening. The breakthrough cancer pain score should be ≥4 assessed by NRS. In the past 7 days, the subject must experience an average of 1 to 4 episodes of breakthrough cancer pain per day, and use 5 mg immediate release morphine at least or equivalent short-acting opioids (e.g., oxycodone, hydrocodone ketones or codeine) to control this pain. ECOG status of 0 to 2. Life expectancy should be longer than 3 months. Subjects must consent to take adequate contraception within the study and 1 months after the study. Women of childbearing potential must show negative in the pregnancy test before dosing. The subject must be able to understand the requirements of the study and provide a written informed consent. Exclusion Criteria: Allergies, or a history of drug allergies to fentanyl. On intrathecal or epidural opioids. HGB < 80 g/L, NEUT ≤1.5 × l09/L, PLT ≤50 × l09/L；ALT and AST higher than 3 times of ULN;total bilirubin and Cr higher than 1.5 times of ULN;PaO2 <95%;FEV1/FVC<70% and FEV1 accounted for less than 80% of the predicted value. Any uncontrolled disease (e.g., severe mental, neurological, infectious, cardiovascular, respiratory and other systemic diseases). Hepatitis B surface antigen and hepatitis C surface antibody positive. Human T Lymphotropic Virus Type I Positive. HIV positive. Gastrointestinal bleeding or diarrhea presently. Requirement of continuous paracentesis. Tumor infiltration to central nervous system. Subjects are not able to slef evaluate pain intensity using NRS Receive surgery in past 3 weeks. Treatment with any form of radiotherapy winth 1week prior to study entry that could alter pain or response to pain medication. Taking monoamine oxidase inhibitors(MAOIs), CYP3A4 inhibitors or inducers within 14 days of the screening Participated in other clinical trials in past 1months. Pregnancy and breast-feeding women, women of childbearing age ready to conceive, and pregnancy test positive. Other conditions that may affect the informed consent, compliance with the protocol, study results and safety of the subject.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled fentanyl aerosol<br>Participants in the stage I were randomized to 6 BTP episodes, in which 4 BTP episodes were treated with inhale fentanyl aerosol (with a starting dose of 25 µg every 4 minutes until adequate pain alleviation. The maximum doses are 6×25 µg) and 2 BTP episodes with placebo(0 µg every 4 minutes until adequate pain alleviation. The maximum doses are 6×0µg) in a random sequence. | Drug: Inhaled fentanyl aerosol<br>* Participants in the stage I were randomized to 6 BTP episodes, in which 4 BTP episodes were treated with inhale fentanyl aerosol (with a starting dose of 25 µg every 4 minutes until adequate pain alleviation. The maximum doses are 6×25 µg) and 2 BTP episodes with placebo(0 µg every 4 minutes until adequate pain alleviation. The maximum doses are 6×0µg) in a random sequence.<br>|
| Experimental: Placebo<br>Participants in the stage I were randomized to 6 BTP episodes, in which 2 BTP episodes were treated with placebo (0 µg every 4 minutes until adequate pain alleviation. The maximum doses are 6×0µg) in a random sequence. | Drug: Placebo<br>* Participants in the stage Ⅰ were randomized to 6 BTP episodes, in which 2 BTP episodes were treated with placebo (0 µg every 4 minutes until adequate pain alleviation. The maximum doses are 6×0µg) in a random sequence. I<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SPID30 | Weighted sum of pain intensity difference at post dose 30 minutes.Pain intensity at each breakthrough pain (BTP) episode at 0 ,4,8,12,16,20 and 30 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. PID30 is calculated as the difference in pain intensity from time 0 to 30 minutes. A positive value is a decrease (improvement) of the pain.SPID30=PID4*4+PID8*4+PID12*4+PID16*4+PID20*4+PID30*10 | During the stage I, at each episode of breakthrough pain, 30 minutes after first dose of study drug. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity at 0, 4,8,12,16,20,30 and 60 minutes post-dose | Pain intensity at each breakthrough pain (BTP) episode at 0 ,4,8,12,16,20, 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.A positive value is a decrease (improvement) of the pain. | During the stage I, at each episode of breakthrough pain, 60 minutes after first dose of study drug. | 
| SPID60 | Weighted sum of pain intensity difference at post dose 60 minutes.Pain intensity at each breakthrough pain (BTP) episode at 0 ,4,8,12,16,20, 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. PID60 is calculated as the difference in pain intensity from time 0 to 60 minutes. A positive value is a decrease (improvement) of the pain.SPID60=PID4*4+PID8*4+PID12*4+PID16*4+PID20*4+PID30*10+PID30*30 | During the stage I, at each episode of breakthrough pain, 60 minutes after first dose of study drug. | 
| Percentage of episodes with NRS≤3 | 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 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. | Through study completion, an average of 4 days | 
| Percentage of episodes with at least 33% and 50%decrease in 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 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. | Through study completion, an average of 4 days | 
| Rescue medication usage | Only Morphine for injection to be used as rescue medication | Through study completion, an average of 4 days |