This multicenter, randomized, placebo-controlled, double-blind, multiple-crossover study was conducted at 14 centers in China. Patients were supposed to stay at the hospital for no longer than 8 days.

The protocol was approved by Ethics Committee of Sun Yat-sen University Cancer Center Ethics Committee (A2021-038–01, A2021-038-X02 after major amendment). This clinical trial was executed in accordance with the ethical and scientific principles of the Declaration of Helsinki, the International Conference on Harmonization Guideline for Good Clinical Practice (ICH GCP), as well as the applicable requirements of National Medical Products Administration (NMPA) guidelines. Written informed consent was obtained from all patients prior to enrollment. The trail was prospectively registered at ClinicalTrials.gov (registered as NCT05531422 after major amendment, registration date: 6 September 2022; initially registered as NCT04713189, registration date: 14 January 2021).

Adult men or women who had a histologically confirmed diagnosis of cancer, receiving a fixed-schedule opioid regimen at a total daily dose equivalent to or greater than 60 mg oral morphine per day for background pain, and had one to four episodes of moderate to severe (defined as ≥ 4 scores on an 11-point numerical rating scale) BTcP per day were eligible. Background pain must had been well-controlled (scored as ≤ 4 on an 11-point numerical rating scale) for at least 1 week before enrollment. Other key inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, adequate hematologic, hepatic, renal functions and Pulmonary function, willingness and ability to comply with study procedures.

Major exclusion criteria included pregnancy; past inability to tolerate fentanyl or other opioids,; severe clinical conditions including brain metastases, myasthenia gravis, bronchial asthma; history of operation within 3 weeks; use of treatment (such as chemotherapy) within 1 week that might impact the patient’s assessment of pain or response to pain medication; use of monoamine oxidase inhibitors within 2 weeks; participation of any other clinical studies within 1 month; inability to assess and score the intensity of pain independently.

Consenting patients who met eligibility criteria were allowed to enter the study. Medication for background pain during screening were maintained until the end of the study. Each patient would be treated and observed in sites for 6 episodes of targeted BTcP. Patients were randomly assigned to 1 of the 6 prespecified dose sequences which were established by a computer-generated schedule of active drug and placebo in a 4:2 ratio. All patients and personnel involved with the study (including investigators and investigative site personnel) were blinded to the medication codes. The randomization codes for each study sites were kept in sealed envelopes (one per drug pack), to be opened only in medical emergencies.

Patients were admitted to centers at Day1, received study medication for all 6 episodes, finished the end-of-study visit within 48 h after last dose, then got permission to leave. Before the first dose of study medication, every patient would take training for breathing maneuver and be taught how to use the device properly. Patients were instructed to exhale fully, then inhale briskly and completely through the device, and hold that breath for 10 s. During each episode of targeted BTcP, patients were allowed up to 6 inhalations with an interval of at least 4 min. The treatment of one episode ended when pain intensity was NRS (numerical rating scale) ≤ 3. A maximum of 4 episodes of BTcP per day could be treated with study drugs with an interval of at least 2 h between episodes.

If the patients did not perceive adequate pain relief 30 min after dosing, they were allowed to take a dose of their usual rescue medication (i.e. subcutaneous injection of morphine). Patients also were instructed that an interval of at least 4 h was to elapse between the use of rescue medication and the next dose of study drug. Any occurrence of acute pain other than the target BTcP could be treated using rescue medication.

Electronic data capture system was used to collect patient data during the study. Baseline pain intensity (PI) before treating an episode of BTcP was recorded using an 11-point NRS (“0” = no pain,“10” = worst pain conceivable). Pain intensity scores were then self-assessed and recorded at 4, 8, 12, 16, 20, 30 and 60 min after the first dosing of each targeted episodes. Pain relief (PR) was assessed before and 30 min after the first dosing using a 5-point categorical scale (1 = no relief; 2 = a little relief; 3 = moderate relief; 4 = a lot of relief; 5 = complete relief). Details of any rescue medication were required, including time of usage and dose.

Safety and tolerability were assessed by monitoring adverse events throughout the study, clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis), measurement of vital signs (heart rate, blood pressure, respiratory rate, and temperature), oxygen saturation, physical examination and cardio-pulmonary function (pulmonary function tests, oxygen saturation and electrocardiogram). Blood samples for clinical laboratory evaluations and cardio-pulmonary function tests were taken during screening and within 48 h after the end of treatment. Vital signs and oxygen saturations were recorded at baseline, 15 min, 30 min, 1 h and 2 h after last dose of every targeted episode. Any change was noted, and the clinical significance of any abnormal findings was judged. Concomitant medications were monitored throughout the study.

In this phase 2 study, we planned to recruit a total of 60 patients.

All statistical analyses were performed by using SAS version 9.4 (SAS Institute, Inc, Cary, North Carolina). Efficacy analysis was primarily performed on full analysis set (FAS) population, which was defined as all randomized patients who received study medication and had ≥ 1 subsequent pain assessment. Safety analyses were performed on safety population, which was defined as all patients who received ≥ 1 of study medication.

The primary endpoint was the SPID at 30 min (SPID30). SPID30 was calculated as the time-weighted sum of PID scores at 30 min, and derived as follows: SPID30 = (PID4 × 4 + PID8 × 4 + PID12 × 4 + PID16 × 4 + PID20 × 4 + PID30 × 10). SPID is widely reported in clinical trials of pain, which summarizes treatment response over a clinically relevant period. The specific calculation formula varies based on the design of different trials.

Secondary efficacy endpoints included: PID (pain intensity difference between each time points and pre-dose) at 4, 8, 12, 16, 20, 30, and 60 min after first inhalation of each episode; SPID at 60 min; the proportion of BTcP episodes with an pain intensity ≤ 3, and with an improvement in pain intensity scores > 33% and > 50% after dosing; PR score at 30 min; and the proportion of BTcP episodes requiring rescue medication.

Linear interpolation method and last-observation-carried-forward (LOCF) method were used to input missing PI scores and PI scores after rescue medication intake. The primary efficacy parameter, SPID30, was analyzed using a mixed model of repeated measures with treatment (fentanyl or placebo), BTcP episode and baseline pain intensity score as fixed factors, and subject as random factor. Secondary endpoints including differences in PID between treatments at each time point, SPID60 and PR30 were analyzed using a model similar to the primary endpoint. In addition, the number and percentage of episodes in each treatment group achieving PI scores ≤ 3 and with an improvement in PI scores > 33% and > 50% were summarized and compared between treatments. Descriptive statistics were used for the description of the study population, baseline characteristics, and safety parameters.

Report of this study was organized following CONSORT reporting guidelines [14].