Zopiclone versus placebo for short-term treatment of insomnia in patients with advanced cancer: study protocol for a double-blind, randomized, placebo-controlled, clinical multicenter trial

This study is designed as a randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase IV clinical trial.

The primary objective is to study the short-time effectiveness of zopiclone on patient-reported subjective sleep quality in patients with advanced cancer who report insomnia. The primary endpoint is patient-reported sleep quality during the final study night with treatment (night 6) assessed on a numerical rating scale (NRS) of 0–10, where 0 = Best sleep and 10 = Worst possible sleep. The secondary objective is to study the effectiveness of zopiclone on mean self-reported total sleep time and sleep onset latency. Table 1 summarizes the objectives and endpoints including the explorative objectives.

The primary variable used in the sample size calculation is patient-reported sleep quality on an NRS of 0–10 during night 6 (the last study night with treatment). The defined minimal clinical important difference (MCID) between the two study groups (zopiclone/placebo) is 2 for the primary outcome sleep quality, scored on the NRS. Due to the lack of relevant data for MCID for NRS on sleep quality, this number was chosen based upon NRS in cancer pain studies [25, 26]. Data obtained in recent studies suggest an expected standard deviation of 2.75 [27‐33]. Using a significance level of 5%, these assumptions indicate that for 80% power 33 patients are needed in each group. For 90% power a sample size of 42 per group is required. The study will aim for a 90% power and allow for an expected number of 8 drop-outs during the study period (6 nights). The study will include 50 patients in each treatment arm.

Patients with advanced cancer with insomnia syndrome will be recruited by study personnel from three outpatient units at hospitals in Norway. Cancer patients are screened using the following two questions: “Do you have problems with your sleep or sleep disturbance on average for 3 or more nights a week?” “Does the problem with your sleep negatively affect your daytime functioning?” Informed consent will be obtained for all patients included in the study.

Patients who have consented to participate in the study will be randomized using a web-based randomization system developed and administered by the Unit for Applied Clinical Research, Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. Patients are randomized to either the zopiclone arm (Arm A) or the placebo arm (Arm B) (Fig. 1). Randomization will be stratified based on study center. Patients are allocated with equal probabilities to treatment. The treatment is double-blind; i.e., the investigational medicinal product (IMP) is blinded for the patient, site, and study personnel by identical appearance, shape, and color as well as identical labeling and packing. In a medical emergency, the investigator will be able to break the code for an individual patient by contacting the person on call at the hospital pharmacy. The external monitor for the trial is the Unit for Applied Clinical Research, NTNU.

The treatment is 6 subsequent nights with zopiclone or placebo. For this study, zopiclone “Actavis” 3.75 mg, 5 mg, and 7.5 mg (active comparator) are defined as the IMP. Kragerø Tablettproduksjon AS, Kragerø, Norway will produce, blind, pack, and label the IMP. Patients will receive the IMP in custom-made capsules containing zopiclone Actavis 3.75 mg, 5 mg, or 7.5 mg or placebo administered once daily (taken in the evening 30 min before going to bed). Each patient will receive six boxes, with each box containing the allocated IMP for 2 nights. Each box is labeled with dose level according to the titration. The initial dose of zopiclone/placebo is 3.75 mg/day started after 1 night with sleep quality assessment and symptom assessment. The study personnel will evaluate the patient by phone after 2 and 4 nights of being on study medication by asking the question “Please circle the number that best describes how you feel now” on an NRS, where 0 = Best sleep and 10 = Worst possible sleep. If the NRS value is ≥4 at evaluation (Fig. 2), the dose of zopiclone/placebo is increased one dose level according to dose level 1 = 3.75 mg zopiclone/placebo; dose level 2 = 5 mg zopiclone/placebo; dose level 3 = 7.5 mg zopiclone/placebo. If NRS is < 4 at evaluation, the patient continues on the same dose level. If patients titrated to dose level 2 at night 4 experience excess sedation during the daytime, the dose can be decreased to dose level 1 for nights 5 and 6. The patients will indicate in the sleep diary whether they have taken their trial drug or not and state the reason, given by the alternatives forgotten, side effects, or other, if they omitted the trial medication. Each patient will be instructed to contact the investigator immediately should they manifest any signs or symptoms they perceive as serious. End-of-protocol therapy is defined as therapy after 6 nights with treatment. Further treatment is the responsibility of the physician in charge of patient treatment. The protocol was considered as a low-risk study, and according to Norwegian legislations, a data monitoring committee was not needed.

Patients may withdraw from the trial at any time at their own request. Patients can be withdrawn from the study at the discretion of the treating physician if they have an acute complication of the cancer or the treatment, including sudden changes in their clinical condition such as cardiovascular events or sepsis.

The following variables will be recorded in the web-based case report form, which is administered by the Unit for Applied Clinical Research, (NTNU): date of birth, weight, height, concomitant diseases, psychiatric history, department category (i.e., palliative care unit or general oncology ward), principal cancer diagnosis (International Classification of Diseases (ICD-10)), date of the principal cancer diagnosis, site of metastases (bone, liver, lung, central nervous system, other), present anticancer treatment, and medications taken in the last 24 h. The Karnofsky Performance Status (KPS) scale will be used to assess performance status [34]. In addition, history and duration of opioid consumption will be obtained. Clinical chemistry results (hemoglobin, creatinine, C-reactive protein, albumin, and bilirubin) will be obtained from the medical record. Results collected less than 7 days before inclusion are considered valid.

The following populations will be considered for the analyses: (1) intention-to-treat population: all randomized patients regardless of protocol adherence; (2) per-protocol population: includes all subjects who have completed the study medication. A safety analysis will be performed, which includes all subjects who have received at least one dose of study medication. Subjects who withdraw from the study will be included in the safety analysis. The main statistical analysis will be performed when the target number of 100 patients has been recruited. Baseline characteristics will be summarized by mean and standard deviations (SDs) for continuous variables, and counts and percentages for categorical variables. The 11-point NRS for sleep quality is regarded as continuous. Comparison of means will be performed with the Student’s t test for continuous variables. The study follows the Consolidated Standards of Reporting Trials (CONSORT) recommendations for reporting RCTs. A p value of ≤0.05 will be considered statistically significant when comparing the two groups for the primary endpoint or the two secondary endpoints. Statistical analyses will be performed with SPSS version 25, IBM Statistics, Chicago, IL, USA.

The SPIRIT schedule (Fig. 3) illustrates the schedule of the trial procedures from baseline to end of study.

Actigraphy is a method of assessment that distinguishes between wakefulness and sleep from the presence or absence of limb movement [44]. The Actiwatch is a small wristwatch-sized device which is used to assess sleep-wake cycles [45]. It has been demonstrated that actigraphy sleep measures are sensitive enough to detect changes related to drug interventions [45]. In this trial, Actiwatch 2 (Philips Respironics, Inc., Murrysville, PA, USA) will be used to collect actigraphy data. Sleep will be measured in one night without study treatment, and then the actigraphy will monitor sleep continuously during the 6 nights in the treatment period (nights 1–6). Data will be analyzed with Actiwatch Spectrum and the latest version of Actiware software. The medium sensitivity setting will be used with an epoch length (i.e., the period of time that the actigraphy data is averaged) of 30 s [46].

The sponsor is St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. Study personnel at the European Palliative Care Research Centre (PRC), NTNU are responsible for the data management for the study. The principal investigator has insurance coverage for this study through membership in the Drug Liability Association, Norway. The patients included in the study will be covered by this insurance.

Participant recruitment is ongoing. Recruitment to the trial started in November 2016. In May 2017, it was decided to accept that both patients treated with an opioid and those not using an opioid can be included in the clinical trial. For this reason, the inclusion criterion “Regularly scheduled oral, subcutaneous, transdermal, or intravenous opioid treatment dose corresponding to step III at the WHO pain ladder with a stable dose for at least 2 days” was deleted from the protocol. The Regional Committee for Medical and Health Research Ethics, Norway approved this amendment in June 2017. The estimated date of completed recruitment is December 2019.