Randomised controlled trial on the effect of internet-delivered computerised cognitive–behavioural therapy on patients with insomnia who remain symptomatic following hypnotics: a study protocol

Introduction Insomnia has severe consequences for health. Primary care physicians in Japan commonly provide hypnotics, which is far from optimal. The recommended treatment for insomnia is cognitive–behavioural therapy (CBT). Access to trained therapists, however, is limited. Rather than face-to-face CBT, several researchers have studied internet-delivered computerised CBT (ICBT). This paper describes the study protocol for a randomised controlled trial (RCT) to evaluate effectiveness and feasibility of our newly developed five-step ICBT as an adjunct to usual care (UC) compared with UC alone for patients with insomnia who remain symptomatic following hypnotics. Methods and analysis This proposed exploratory RCT comprises two parallel groups (ICBT+UC and UC alone) consisting of 15 participants each (n=30) diagnosed with insomnia who remain symptomatic after pharmacotherapy. We aim to evaluate the effectiveness of six intervention weeks. The primary outcome of insomnia severity will be the Pittsburgh Sleep Quality Index (PSQI) at week 6. Secondary outcomes include sleep onset latency, total sleep time, sleep efficiency extracted from PSQI, current feeling of refreshment and perceived soundness of sleep measured using visual analogue scale, number of awakenings, anxiety by Hospital Anxiety and Depression Scale, depression by Center for Epidemiologic Studies Depression Scale and quality of life by Euro Qol-5D. All measures will be assessed at weeks 0 (baseline), 6 (postintervention) and 12 (follow-up), and intention-to-treat analysis will be applied. The statistical analysis plan has been developed considering design of field materials. Ethics and dissemination This study will be conducted at the academic outpatient clinic of Chiba University Hospital, Japan. Ethics approval was granted by the Institutional Review Board of Chiba University Hospital. All participants will be required to provide written informed consent. The trial will be implemented and reported in accordance with Consolidated Standards of Reporting Trials recommendations. Trial registration number UMIN000021509; Pre-results.

3. An exploratory study by Vallières et al. (2005) suggested that pharmacotherapy prior to the initiation of CBT appears to be less effective. The authors should discuss sequential combinations of drug and CBT.

REVIEWER
Tanja van der Zweerde Phd-student Department of Clinical Psychology VU University Amsterdam The Netherlands REVIEW RETURNED 24-Aug-2017

GENERAL COMMENTS
Thank you for the opportunity to review your article. I find it a very interesting topic, and your aim of offering better treatment to people suffering from insomnia is one I share with you. I have some comments that I hope you will find of use. Your protocol seems well thought-out and the article presents your design very concisely. A few points of consideration. 1) You mention chronobiological treatment as a treatment option that has been experimentally verified very briefly. I would suggest either elaborating some more, or alternatively leaving it out, as your main focus is on CBT.
2) I would like to see a definition of sleep-medication resistance, which makes clearer to the reader who your intended participants are. "Remaining symptomatic" should be defined more clearly.

Response
Thank you for your detailed comment. We have added the description in Introduction (Pharmacotherapy for insomnia), "Clinical practice guidelines suggest CBT, rather than pharmacotherapy, as the initial therapy for patients with insomnia.".
Comment #1-2 Although the authors mentioned chronobiological treatment to enhance regular input into the body's circadian rhythms by use of bright light, the evidence is not as strong as CBT. In the introduction, the authors should describe effectiveness of light therapy, compared with CBT or pharmacotherapy.

Response
We have added the description in Introduction (Pharmacotherapy for insomnia), "It has been reported that compared with CBT, the effect of light therapy on sleep maintenance is lower.". Comment #1-3 An exploratory study by Vallières et al. (2005) suggested that pharmacotherapy prior to the initiation of CBT appears to be less effective. The authors should discuss sequential combinations of drug and CBT.

Response
We have added the description in Introduction (Pharmacotherapy for insomnia), "Vallières reported that pharmacotherapy prior to the initiation of CBT appears to be less effective than the combined treatment of pharmacotherapy and CBT, followed by CBT alone. This study also found that early introduction of CBT contributes to maximizing the effect of pharmacotherapy.".

Response to Comments from Reviewer 2
Comment #2-1 You mention chronobiological treatment as a treatment option that has been experimentally verified very briefly. I would suggest either elaborating some more, or alternatively leaving it out, as your main focus is on CBT.

Response
We have added the description in Introduction (Pharmacotherapy for insomnia), "It has been reported that compared with CBT, the effect of light therapy on sleep maintenance is lower.".
Comment #2-2 I would like to see a definition of sleep-medication resistance, which makes clearer to the reader who your intended participants are. "Remaining symptomatic" should be defined more clearly. In addition, I think more information is needed on what treatment history the intended participants should have had (i.e. medication, but for how long, dosage, type of drug, several attempted sleep drugs, etc.). Are participants allowed to keep using medication while undergoing CBTI?

Response
We have modified the description in Methods and Analysis (Participants), ""Remaining symptomatic" is defined herein as having insomnia that is at least moderate in severity, based on a PSQI score of >5.5, after the use of hypnotics including non-benzodiazepines, benzodiazepines, melatonin receptor agonists, orexin receptor antagonists, and antidepressants.".
Participants are allowed to keep using medication during this study period". We have changed the word in Methods and Analysis (Interventions, UC), "hypnotics" instead of "medication". Response That is as you pointed out. There is a possibility for improvement of control group. We have added additional comments on the limitations of the study in Discussion, "The third limitation is that there is a possibility for improvement of control group as ICBT is provided to the applicant of the control group after the end of the follow-up period." Comment #2-4 Sleep restriction therapy, sleep hygiene education and stimulus control treatment are mentioned but not explained. I believe these are not self-explanatory and deserve elaboration.

Response
We have added the description in Introduction (CBT for insomnia), "Sleep restriction therapy is an approach designed to reduce the time in bed to the actual time of sleep being achieved", "Stimulus control treatment is behavioral directions to associate the bed with sleep and to restore a consistent sleep rhythm", and "Sleep hygiene education includes health practices such as physical exercise and environmental correlates such as light that may further or disturb sleep".
Comment #2-5 Will participants in the control group also be offered the CBTI treatment after the trial, if the usual care (as you expect) will not have made them sleep better? I think this would be advisable from a ethical viewpoint.