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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Age of 18 to 75years, inclusive.
2. Subjects must be diagnosed with cancer.
3. 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.
4. Subjects must experience persistent pain associated with cancer, and the pain score assessed by NRS should be \<4 within 24hour before screening.
5. The breakthrough cancer pain score should be ≥4 assessed by NRS.
6. 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.
7. ECOG status of 0 to 2.
8. Life expectancy should be longer than 3 months.
9. 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.
10. The subject must be able to understand the requirements of the study and provide a written informed consent.

Exclusion Criteria:

1. Allergies, or a history of drug allergies to fentanyl.
2. On intrathecal or epidural opioids.
3. 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.
4. Any uncontrolled disease (e.g., severe mental, neurological, infectious, cardiovascular, respiratory and other systemic diseases).
5. Hepatitis B surface antigen and hepatitis C surface antibody positive. Human T Lymphotropic Virus Type I Positive. HIV positive.
6. Gastrointestinal bleeding or diarrhea presently.
7. Requirement of continuous paracentesis.
8. Tumor infiltration to central nervous system.
9. Subjects are not able to slef evaluate pain intensity using NRS
10. Receive surgery in past 3 weeks.
11. Treatment with any form of radiotherapy winth 1week prior to study entry that could alter pain or response to pain medication.
12. Taking monoamine oxidase inhibitors(MAOIs), CYP3A4 inhibitors or inducers within 14 days of the screening
13. Participated in other clinical trials in past 1months.
14. Pregnancy and breast-feeding women, women of childbearing age ready to conceive, and pregnancy test positive.
15. Other conditions that may affect the informed consent, compliance with the protocol, study results and safety of the subject.