Feasibility Study of Personalized Trials to Improve Sleep Quality

Re-engineering Precision Therapeutics Through N-of-1 Trials: Feasibility Study of Personalized Trials to Improve Sleep Quality

The purpose of this pilot study is to assess the feasibility of using N-of-1 methods in a virtual research study of melatonin intervention for poor sleep quality. Participants (N=60) will be sent a Fitbit device and 3 smart pill bottles, with one containing 3 mg of melatonin, one containing 0.5 mg of melatonin, and the final bottle containing a placebo pill. The first two weeks will be a baseline period, where no supplement is assigned, but data are collected, including self-report of sleep quality and duration and accelerometer-derived sleep and activity data. After successful completion of the baseline period, participants will be randomized to six 2-week intervention blocks of a 3 mg dose melatonin, a 0.5 mg dose melatonin, and a placebo. At the end of the trial, participants will be asked to complete the System Usability Scale, a satisfaction survey (electronic or phone/video call if they are non-responders), and participate in a virtual interview (such as over Microsoft Teams or a phone call) to inform feasibility and acceptability of protocol requirements, study materials, and personalized reports.

The purpose of this pilot study is to assess the feasibility of using N-of-1 methods in a virtual research study; to remotely recruit and enroll participants; to assess the feasibility of using a placebo and to determine the feasibility of the proposed methods used to collect and assess participant adherence and response to a wellness strategy (in this case, melatonin for poor sleep quality). This pilot will help determine if an N-of-1 study design, or what has been termed 'Personalized Trials', can have widespread use in future research and clinical practice to address high public health burdens with a high heterogeneity of response. This pilot study will assess feasibility using a Personalized Trials model to evaluate an individual participant's experience with a wellness strategy for self-reported poor sleep quality. Participants (N=60) will be sent a Fitbit device and 3 smart pill bottles, with one containing 3 mg of melatonin, one containing 0.5 mg of melatonin, and the final bottle containing placebo pills. Participants will be asked several questions a day sent via text message about their sleep quality, as well as their stress, fatigue, concentration, confidence, mood, and pain levels to demonstrate relevant secondary impacts of sleep quality. Participants will also have access to several videos explaining the protocol. The study will take place over the course of 14 weeks. The first two weeks will be a baseline period, where no supplement is assigned, but data are collected, including self-report of sleep quality and duration and accelerometer-derived sleep and activity data. After successful completion of the baseline period, participants will be randomized to six 2-week intervention blocks of a 3 mg dose melatonin, a 0.5 mg dose melatonin, and a placebo. At the end of the 14 weeks, a report containing the individual's observed data will be prepared for each participant and electronically sent to them along with a satisfaction survey (electronic, or phone/video call if they are non-responders). After the end of the 14-week trial, participants will receive a summary of their observed data in a personalized report. Creating this type of report will help to assess the feasibility of using a N-of-1 trial design through user-acceptability of sleep quality and wellness-related data visualizations, and the ability to choose preferred intervention (if any) based on the data. Participants will be asked to complete the System Usability Scale, a satisfaction survey (electronic or phone/video call if they are non-responders), and participate in a virtual interview (such as over Microsoft Teams or a phone call) to inform feasibility and acceptability of protocol requirements, study materials, and personalized reports.

Individuals will receive a kit with medication adherence devices containing melatonin 3 mg in one of three smart electronic pill bottles labeled "A," "B," and "C." Participants will not be aware which of the pill bottles contains the 3mg of melatonin. Participants will be randomized to take pills in 6 alternating intervention periods 2 weeks in length. During periods where participants were randomized to receive melatonin 3 mg, they will receive a nightly text notification 1 hour before bed instructing them to take a pill from the corresponding smart pill bottle. The melatonin 3 mg intervention will be administered in 2 intervention periods each 2 weeks in length (4 weeks total).

Individuals will receive a kit with medication adherence devices containing melatonin 0.5 mg in one of three smart electronic pill bottles labeled "A," "B," and "C." Participants will not be aware which of the pill bottles contains the 0.5 mg of melatonin. Participants will be randomized to take pills in 6 alternating intervention periods 2 weeks in length. During periods where participants were randomized to receive melatonin 0.5 mg, they will receive a nightly text notification 1 hour before bed instructing them to take a pill from the corresponding smart pill bottle. The melatonin 0.5 mg intervention will be administered in 2 intervention periods each 2 weeks in length (4 weeks total).

Individuals will receive a kit with medication adherence devices containing the placebo pills in one of three smart electronic pill bottles labeled "A," "B," and "C." Participants will not be aware which of the pill bottles contains the placebo. Participants will be randomized to take pills in 6 alternating intervention periods 2 weeks in length. During periods where participants were randomized to receive the placebo, they will receive a nightly text notification 1 hour before bed instructing them to take a pill from the corresponding smart pill bottle. The placebo will be administered in 2 intervention periods each 2 weeks in length (4 weeks total).

Participants will be provided with a smart pill bottle containing a 4-week supply of 3 mg melatonin pills.

Participants will be provided with a smart pill bottle containing a 4-week supply of 0.5 mg melatonin pills.

Participants will be provided with a smart pill bottle containing a 4-week supply of cellulose placebo pills.

The SUS is a validated 10-item questionnaire that asks users to score each item on a Likert scale from Strongly Disagree (rating of 1) to Strongly Agree (rating of 5). The SUS will be presented to the participant as addressing the ease of use, complexity, consistency of the Personalized Trials system as a whole, from recruitment to receipt of the report. Individual results are calculated to arrive at a composite measure out of 100. Participant SUS scores will be averaged together and an overall mean will be reported with standard deviation. Higher scored values correlate to a more usable system, and therefore a better outcome.

Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

Participants will rate their satisfaction with the Personalized N-of-1 Trial overall and with individual elements of the trial in a satisfaction survey administered following the baseline and intervention periods (14 weeks). Means and standard deviations will be reported for each element of satisfaction. Participants will rate their satisfaction on a scale of 1 to 5, with higher scores indicating greater levels of satisfaction.

Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

Nightly sleep duration will be assessed by a Fitbit wearable device. Sleep duration will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Sleep duration values over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

Nightly sleep duration will be assessed consistently via Fitbit device during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

Participants will rate their sleep disturbance using a modified version of the Consensus Sleep Diary administered daily during baseline and intervention periods (14 weeks). Participants will be asked to rate their sleep on a 5-point scale rated from "very poor" to "very good". Levels of daily sleep quality will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period, with higher scores indicating better sleep quality. Changes in sleep quality over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

Daily sleep quality will be assessed daily via survey during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each).

Fatigue will be assessed via 3 daily text message prompts sent at random times throughout the day asking individuals to rate their fatigue on a scale of 0(low) to 10(high). Levels of EMA fatigue will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Changes in EMA fatigue over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

EMA fatigue will be assessed 3 times daily via text message during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

Stress will be assessed via 3 daily text message prompts sent at random times throughout the day asking individuals to rate their fatigue on a scale of 0(low) to 10(high). Levels of EMA stress will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Changes in EMA stress over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

EMA stress will be assessed 3 times daily via text message during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

For each participant, the proportion of days where the Fitbit device was worn will be calculated. Proportion of days where the Fitbit device was worn across all participants will be reported with means and standard deviations.

Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

For each participant, the proportion of days where the melatonin 0.5 mg supplement was administered will be calculated. Proportion of days adherent across all participants will be reported with means and standard deviations.

: Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

For each participant, the proportion of days where the melatonin 3 mg supplement was administered will be calculated. Proportion of days adherent across all participants will be reported with means and standard deviations.

Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

For each participant, the proportion of days where the placebo supplement was administered will be calculated. Proportion of days adherent across all participants will be reported with means and standard deviations.

Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

Participants will rate their sleep disturbance using the Insomnia Severity Index (ISI) administered daily during baseline and intervention periods (14 weeks). Items are rated from 0 to 4, with higher scores indicating greater levels of sleep disturbance. Levels of daily sleep disturbance will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Changes in sleep disturbance over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

Difference in self-reported sleep disturbance will be assessed every two weeks between baseline and intervention periods (14 weeks total).

Participant self-reported side effects will be assessed utilizing a weekly survey measure. Number of side effects will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate a count of self-reported side effects in each study period. Side effects over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

Self-reported side effects will be assessed via weekly survey during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

. Pain will be assessed via 3 daily text message prompts sent at random times throughout the day asking individuals to rate their pain on a scale of 0(low) to 10(high). Levels of EMA pain will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Changes in EMA pain over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

EMA pain will be assessed 3 times daily via text message during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

Mood will be assessed via 3 daily text message prompts sent at random times throughout the day asking individuals to rate their fatigue on a scale of 0(poor) to 10(excellent). Levels of EMA mood will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Changes in EMA mood over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

EMA mood will be assessed 3 times daily via text message during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

Concentration will be assessed via 3 daily text message prompts sent at random times throughout the day asking individuals to rate their fatigue on a scale of 0(low) to 10(high). Levels of EMA concentration will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Changes in EMA concentration over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

EMA concentration will be assessed 3 times daily via text message during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

Confidence will be assessed via 3 daily text message prompts sent at random times throughout the day asking individuals to rate their fatigue on a scale of 0(low) to 10(high). Levels of EMA confidence will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Changes in EMA confidence over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

EMA confidence will be assessed 3 times daily via text message during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

. Daily step counts will be assessed by a Fitbit device. Daily step counts will be aggregated within the baseline assessment period and in each of the intervention periods (3 mg melatonin, 0.5 mg melatonin, placebo) to generate an overall mean and standard deviation for each period. Daily steps values over the course of the study will be evaluated using Generalized Linear Mixed Model analyses.

Daily steps will be assessed consistently via Fitbit device during the baseline assessment period (2 weeks) and during each of the 6 intervention periods (2 weeks each, 12 weeks total).

For each participant of the proportion of surveys measures completed (both daily and weekly surveys) will be calculated. Proportion of days adherent across all participants will be reported with means and standard deviations.

Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

For each participant of the proportion of EMA measures completed will be calculated. Proportion of days adherent across all participants will be reported with means and standard deviations.

Assessed once after the results report has been sent to the participant after completion of the trial (14 weeks from baseline).

Inclusion Criteria: Age ≥ 18 years Fluent in English Ability to take melatonin and a placebo Self-report of disrupted sleep symptoms using the Insomnia Symptom Questionnaire (ISQ) Owns and can regularly access a smartphone capable of receiving text messages Owns and can regularly access an e-mail account Lives in the United States Agreement to adhere to lifestyle considerations including wearing a Fitbit device day and night and potentially adapting their current melatonin routine to fit the protocol throughout study duration Exclusion Criteria: Age < 18 years old Women who are pregnant or breastfeeding Individuals diagnosed with depression, seasonal affective disorder, schizophrenia, autoimmune disease, or asthma Individuals taking MAO inhibitors or corticosteroids Individuals diagnosed with low blood pressure Clinical diagnosis of a sleep disorder (e.g., Narcolepsy, Circadian Rhythm Sleep-Wake Disorders, Periodic Limb Movement Disorder, Restless Leg Syndrome, Obstructive Sleep Apnea etc.) Deemed unable to complete the study protocol as a result of cognitive impairment, severe medical or mental illness, or active or prior substance abuse Participation in shift work (evening/night shifts, early morning shifts, rotating shifts, etc.) Pilot or flight attendant with frequent travel across time zones Receiving specialty mental health care for insomnia (e.g., cognitive behavioral therapy for insomnia, medications for insomnia) Has even been told by a doctor or healthcare provider that it is not safe to take melatonin Does not own or cannot regularly access a smartphone capable of receiving text messages Does not possess or cannot regularly access an email account Lives outside the United States Planned surgeries within 6 months from study start date

All collected individual participant data (IPD) will be de-identified and pooled before sharing on the Open Science Framework, along with a data dictionary. Supporting Information: Study Protocol, Statistical Analysis Plan (SAP), Informed Consent Form (ICF) Time Frame: The study protocol, including the statistical analysis plan, will be made available in addition to the informed consent form following completion of recruitment but prior to publication of any data from the current study. De-identified, pooled individual participant data will be made available within a year of final participant data collection. We anticipate this data to be available on the Open Science Framework platform indefinitely. Access Criteria: All data and supporting information will be stored on the Open Science Framework, a free web application with no access restrictions.