Oral Nicotinamide Mononucleotide (NMN) to treat chronic insomnia: Protocol for the multicenter, randomized, double-blinded, placebo-controlled trial.

doi:10.21203/rs.3.rs-1872814/v1

Download PDF

Research Article

Oral Nicotinamide Mononucleotide (NMN) to treat chronic insomnia: Protocol for the multicenter, randomized, double-blinded, placebo-controlled trial.

https://doi.org/10.21203/rs.3.rs-1872814/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 18 May, 2023

Read the published version in Trials →

You are reading this latest preprint version

Background: The treatment of insomnia, which is the most common sleep disorder, includes drug and behavioral treatment, but each treatment measure has its limitations. So new treatment method needs to be taken to improve the treatment effect. MN supplementation is a potential promising new method for the treatment of insomnia, resulting in a rising need for methodological research towards verifying its efficacy.

Methods/Design: We describe a proposal for a multicenter, patient-assessor-blinded, randomized controlled trial with two parallel arms. A total of 400 chronic insomnia patients will be allocated 1:1 to the intervention group (treatment with oral NMN 320mg/day) or control group (treatment with oral placebo). All subjects are clinical chronic insomnia patients who meet all inclusion criteria. All subjects are treated by taking NMN or placebo.

The primary outcome is the score on the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes are the score on the Insomnia Severity Index (ISI) and Epworth Sleeping Scale (ESS)，the Total sleep time (TST), sleep efficiency (SE), sleep latency, REM sleep latency to assess sleep quality changes.

Subjects are assessed at two time points: baseline and follow-up. The duration of the clinical trial is 60 days.

Discussion: This study will provide more evidence on the effects of NMNon improving sleep quality among patients with chronic insomnia. If proven effective, NMN supplementcan be used as a new treatment for chronic insomniain the future.

Trial registration:

Chinese Clinical Trial Registry (chictr.org.cn): ChiCTR2200058001. Registered on 26 March 2022.

Chronic insomnia

Nicotinamide mononucleotide (NMN)

Clinical trial

The numbers in curly brackets in this protocol refer to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/ reporting-guidelines/spirit-2013-statement-defining- standard-protocol-items-for-clinical-trials/).

Table 1 Administration Information

Title {1}	Oral Nicotinamide Mononucleotide (NMN) as a treatment for chronic insomnia: protocol for the multicenter, randomized, double blind, placebo-controlled trial.
Trial registration {2a and 2b}	Chinese Clinical Trial Registry (chictr.org.cn): ChiCTR2200058001. Registered on 26 March 2022. ChiCTR2200058001
Protocol version {3}	13 March 2022. Version 1
Funding {4}	This trial is funded by grants from China Health Promotion Foundation
Author details {5a}	Xiangyang Gao，Health Management Institute，The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China. Junhua Li, Health Management Center, Handan Central Hospital, Handan, Hebei Province, China. Sanping Xu, Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province China. Xueying li，Department of Biostatistics, Peking University First Hospital, Beijing 100034, China. Xicheng Wang, Beijing Dublin International Collage, Beijing University of Technology, Beijing 100124, China. Yongli Li，Health Management Center, Henan Provincial People's Hospital, Zhengzhou, China. Yan Huang, Health Management Center, West China hospital, Sichuan University, Chengdu, Sichuan Province, China. Shaohui Liu, Health Management Center, Xiangya hospital, Central south hospital, Changsha, Hunan Province, China. Qiang Zeng，Health Management Institute，The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China.
Name and contact information for the trial sponsor {5b}	This trial is funded and proceeded by China Health Promotion Foundation Wu Shiyong, Room 521,Wankai Road, Fentai District, Beijing, China, +86-13261008988, Email：[email protected]
Role of sponsor {5c}	This trial is solely funded by non-commercial sources. Funding sources have had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.

Background and rationale {6a}

Insomnia

Insomnia refers to persistent challenges in falling asleep, maintaining sleep, or waking up earlier than the habitual rise time, and is associated with the impairment of daytime functioning despite the opportunity for sufficient sleep duration [1]. It is a prevalent condition associated with significant morbidity, reduced productivity, increased risk of accidents, and poor quality of life [2]. The prevalence of insomnia disorder is approximately 10–20%, of which approximately 50% have a chronic course [3]. Based on a meta-analysis of China’s population, the prevalence of insomnia was 15% [4]. Of the of Chinese survey respondents, 45.4% reported varying degrees of insomnia [5]. Insomnia has become the second major reason leads patients to visit neurology clinics, the first one is headaches [6]. Owing to its prevalence, the annual loss of quality-adjusted life-years (QALYs) from insomnia appears to be greater than that from other medical and psychiatric conditions, including arthritis, depression, and hypertension [7]. As the most common sleep disorder, insomnia is a substantial burden on healthcare systems and vulnerable patient groups. The combined direct and indirect costs for insomnia in the United States exceed $100 billion annually [8].

Currently, the prescribed treatment for insomnia primarily involves drug and behavioral treatments, however, they have limitations [9]. Many patients prefer hypnotics to non-drug treatments despite side effects and issues with drug dependence and tolerance because they help reduce sleep latency (SL) and increase total sleep time (TST) at night [10, 11]. Multifactorial behavioral treatments such as cognitive behavioral therapy for insomnia (CBTI), has moderate to great effects on sleep parameters; however, only 26–43% of patients experience complete relief from insomnia [12]. Moreover, the high cost and lack of trained providers of CBTI have prevented widespread uptake [13–15]. Therefore, the public health burden of insomnia is still large and new treatment methods must be developed to improve it.

Insomnia is a complex interaction between psychological cognitive arousal, altered circadian clock and sleep homeostatic mechanisms. Circadian factors promote wakefulness on a roughly 24-hour biological clock, whereas homeostatic factors respond to accumulated wakefulness with the drive for sleep [16, 17]. Disrupted sleep-wake and molecular circadian rhythms are features of aging associated with metabolic diseases and reduced nicotinamide adenine dinucleotide (NAD+) levels [18]. A clue to the mechanism underlying the decline in circadian rhythms and metabolism with age stems from the observation that the longevity-associated deacetylase, SIRT1, interacts with the core clock complex [19, 20]. For SIRT1 activity to occur, the sentinel metabolite NAD+, which declines with age is required. Declining NAD+/SIRT1 leads to the downregulated expression of clock genes, such as BMAL1 and PER2, which affects the internal circadian clock [21–23]. Neural activation dependent on SIRT1 in the dorsomedial hypothalamic nucleus and lateral hypothalamus has been reported to prevent aging-induced decline in the quality of sleep in mice [24]. Nicotinamide mononucleotide (NMN) is an intermediate that effectively improves the level of NAD+ [22], and has been extensively studied over the years [25]. Therefore, NMN supplementation is a promising method to treat insomnia. Recent preclinical studies have demonstrated that administering NMN could compensate for NAD + deficiency and can affect diverse pharmacological activities in various diseases, including diabetes, obesity, ischemia reperfusion injury (IRI), heart failure etc. [26–29] Given that NMN has demonstrated high efficacy and benefits in various mouse models of human disease, several clinical trials have been conducted to investigate its clinical applicability [30, 31]. Therefore, it is necessary to verify the of NMN’s effect on insomnia. This trial aims to prove that NMN supplementation is an effective treatment for therapy chronic insomnia, a subtype of insomnia and refers to symptoms occurring 3 or more times per week for 3 months or longer [16].

Objectives {7}

Our primary objective is to evaluate the efficacy and safety of Nicotinamide Mononucleotide (NMN) as a treatment for chronic insomnia.

Trial design {8}

This trial will be carried out as a multicenter, double blinded randomized controlled trial with a two-group parallel design. Participants (n = 400) will be allocated 1:1 to either oral MNM as treatment (intervention group) or to oral placebo (control group). Outcome assessments will be conducted two times for each participant: at baseline and at follow-up (day 60), as presented in Fig. 1.

Study setting

We will recruit patients from the below nine hospitals:

Health Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Health Management Center, Handan Central Hospital
Health Management Center, The Second Affiliated Hospital of Xi'an Jiaotong University
Health Management Center, Liaoning Electric Power Central Hospital
Health Management Center, The Fourth People's Hospital of Zigong City
Health Management Center, Guang'an People's Hospital
Health Management Center, The Second People's Hospital of Weinan City
Health Management Center, Three Gorges Hospital affiliated to Chongqing University
Health Management Center,Hunan Provincial People's Hospital

Eligibility criteria {10}

Inclusion Criteria

Participants will be included if they:

Age between 18- 65 years.
Clinical diagnosis of chronic insomnia (according to the ICSD-3 criteria for chronic insomnia).
Without hepatorenal and cardiac disfunction (normal laboratory examination, ECG, etc.)
Can be trained and able to use the smart wearable device.
Be able to read, understand, and provide written informed consent before enrolling in the study.
Agree to participate for the entire study period.

Exclusion Criteria

Patients will be excluded if they:

Physical diseases, mental disorders and/or sleep disorders (including patients with restless legs syndrome) that are clearly diagnosed, directly affect sleep, and are not cured.
Received any insomnia drugs and psychotherapy within the preceding one month.
On a continuous current daily intake of nutritional supplements and vitamin supplements.
Pregnant, shift workers, perennial night shift workers, frequent cross time zone pilots (such as crew members of international flights), patients with sleep phase delay syndrome.
Cancer, dyslexia, or lack of self-care ability.
Depression and suicide risk (suicide plan / attempt within the preceding one month).
Regular medicated background systemic chronic diseases, such as hypertension and diabetes.
Hyperuricemia or gout.
Sleep disorders caused by other diseases.

Who will take informed consent? {26a}

The fully trained specific researchers who are on-site will obtain informed consent from participants.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

On the consent form, participants are asked to sign if they agree to have been given written and oral information on the purpose, method, advantages, and disadvantages of saying yes to participate in the trial, and if they agree to participate voluntary. On the consent form, participants are informed that they can withdraw the consent without losing any rights to treatment, either current or future. They are also asked if they agree to the use of their data when they choose to withdraw from the trial.

This trial does not involve collecting biological specimens for storage.

Interventions
Explanation for the choice of comparators {6b}

Participants in the control group will take the oral placebo which is manufactured where same as the intervention oral NMN.

Intervention description {11a}

In this trial, intervention group (n=200) will have oral MNM（320mg/day), 1 tablet bid(each tablet contains 160mg NMN), after the meal for 60 days. Control group (n=200) will have oral placebo, 1 tablet bid, after the meal for 60 days.

Criteria for discontinuing or modifying allocated interventions {11b}

N/A

Strategies to improve adherence to interventions {11c}

Adherence enhancement strategies are in use throughout the trial period, e.g., patients are being reminder of the importance of adhering regardless of allocation via phone call on Day 1, Day3, Day7, Day15, Day30, Day45 and Day60.

Relevant concomitant care permitted or prohibited during the trial {11d}

Throughout the trial period, participants regardless of allocation, who had background disease are permitted to have relevant medicines accordingly but are prohibited from taking together with the intervention. Participants regardless of allocation are prohibited from taking any treatment may impact the objective function e.g., anti-oxide, sleep improvement, visual fatigue reliving, body fatigue reliving).

Provisions for post-trial care

N/A

Outcomes {12}

Primary Outcome

The primary outcome is sleep efficiency at baseline and follow-up on day 61. It will be assessed with the Pittsburgh Sleep Quality Index (PSQI) questionnaire. It includes nine items/18 questions with seven categories, including subjective sleep quality, sleep latency, sleep duration, habitual SE, sleep disturbances, use of sleep medications and daytime dysfunction. A global sum score for the PSQI >5 indicates poor sleep. The Cronbach’s α value for the PSQI is 0.83 [32, 33].

Secondary outcome

Other sleep efficiency indices, including the Epworth Sleeping Scale (ESS) and Insomnia Severity Index (ISI), will be used at the baseline and follow-up on day 61 for the secondary outcome assessment. The ISI is a 7-item self-report questionnaire that assesses the nature, severity, and impact of insomnia. The dimensions are severity of sleep onset, sleep maintenance and early morning waking problems, sleep dis- satisfaction, interference of sleep difficulties with daytime functioning, noticeability of sleep problems by others, and distress caused by sleep difficulties. It is rated on a 5-point Likert scale (total score 0–28). A score of 0–7 indicates absence of insomnia, 8–14 sub- threshold insomnia, 15–21 moderate insomnia, and 22– 28 severe insomnias. Internal consistency is excellent in community as well as clinical samples (Cronbach’s alpha 0.90–0.91 [33, 34]).

Total sleep time (TST), sleep efficiency (SE), sleep latency, REM sleep latency, the percentage of N1, N2, N3 and REM assessed by polysomnography (PSG,Model: NS-100A) will be included as secondary outcome. PSG is a comprehensive study of the biophysiological changes that occur in the human body during sleep. The electrodes will be attached to each participant, recording data from electroencephalogram, eye movements electrooculogram, electromyogram muscle activity or skeletal muscle activation, heart rhythm, respiratory airflow, respiratory effort, and peripheral pulse oximetry. All PSG studies will be conducted in the participants’ own homes. Data from PSG will be analyzed by the researcher.

Laboratory examination including complete blood count, blood biochemical test will be additional information.

Participant timeline

The trial period for each participant is approximately 60days. All participants will complete the same outcome assessments at baseline and at follow-up (Day 61) All participants will complete the same outcome assessments at baseline, as presented in Fig. 1 and Table 2.

Sample size {14}

This trial is designed as a placebo-controlled, parallel group, and superiority trial. The ratio between groups was 1:1; α= 0.05 (bilateral), β= 0.20. According to the pre-test, compared with placebo, the decrease of PSQI score in the treatment group is 1 point higher than that in the control group, and the common standard deviation is about 3.3 points. Thus, by PASS 16.0, 172 effective cases need to be completed in each group. Considering the possible abscission, a total of 400 cases are planned to be enrolled. There were 200 cases in each group.

Recruitment {15}

Participants will be recruited through advertisement and referrals referrals. Ads will be put in social media (e.g., Wechat) and poster and flyers in public places (e.g., health management center, out-patient department). Pharmacists and general practitioners around the trial sites will be contacted for potential referrals.

Assignment of interventions: allocation

Sequence generation {16a}

Randomization will be conducted after baseline assessment by computer-generated random numbers with blocks of ten participants.

Concealment mechanism {16b}

Sealed envelopes according to the random table are prepared. Subjects who met the inclusion criteria open the corresponding sealed envelopes in the order of enrollment and been assigned to the study group according to the assignment on the envelopes.

Implementation {16c}

An external collaborator (statistician) will generate the allocation sequence. This collaborator is not involved in outcome assessments or the intervention. On-site researchers will be responsible for the enrollment and assignment.

Assignment of interventions: Blinding Who will be blinded {17a}

An external collaborator (statistician) will generate the blind codes for intervention and placebo which are identical. Both the investigator and the participants will be blinded at recruitment and during the intervention. Trial participants and care providers will be blinded during the study. The sequence will be stored in a password-protected data management system and cannot be accessed by blinded study staff who have contact with participants.

Procedure for unblinding if needed {17b}

In the event of a serious adverse event (SAE) or reaction, the allocation list will be retrieved to reveal the participant’s allocated treatment during the trial, PI and on-site researchers will be responsible for signature and documentation. The process needs to be reported to Ethics Committee.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Outcome assessors will be fully trained on the questionnaires used in the study, who pass the assessment for assessor can be responsible for outcome assessment. All the involved sites will be calibrated on laboratory test.

Plans to promote participant retention and complete follow-up {18b}

Dates for assessments will be planned by on-site researchers together with each participant, and all participants will be able to connect with the responsible researcher on their telephone or an email. Participants are aware of being able to get allowance when completing all rescheduled follow-up.

Data management

All participants will receive an identification code and all data will be de-identified. A list of identifiable participant information associated with each identification code will be stored electronically separately from the research data for 5 years. Patient- reported information will be completed electronically on a tablet, which will be used only for participants in this trial. A special Electric Data Capture (EDC) will be established for data management.

Confidentiality {27}

All information collected during the trial will be kept confidential. All data will be processed confidentially, personal sensitive data (full name, contact information, ID) will not be included in EDC system.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

There will be no biological specimens collected for genetic or molecular analysis in this trial.

Statistical methods
Statistical methods for primary and secondary outcomes {20a}

The primary outcome variable for efficacy analysis is the Pittsburgh Sleep Quality Index (PSQI); the secondary outcomes are ISI, ESS, TST, sleep efficiency (SE), SL, and rapid eye movement (REM) sleep latency. Demographics, PSQI, ISI, ESS, TST, SE, SL, and REM sleep latency will be analyzed using independent sample t-tests at baseline to determine the equality of the two groups. A chi-square test will be used to assess differences based on sex. An efficacy analysis will be conducted using both per-protocol and intention-to-treat analyses.

The changes in PSQI scores relative to baseline in the two groups after 60 days of treatment were compared using an analysis of the covariance model in which the roles of grouping and center were also considered. The significance level was set at P <0.05 and post hoc analyses were performed where appropriate.

Interim analyses {21b}

This trial is not subject to interim analyses.

Methods for additional analyses (e.g., subgroup analyses) {20b}

We have no intention to conduct subgroup and adjusted analyses.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Data will be analyzed according to Intent-to-Treat Population, last observation carry forward (LOCF) will be used for missing data management.

Plans to give access to the full protocol, participant level-data and statistical code {31c}

The datasets analyzed during this trial are available from the corresponding author on reasonable request.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

A joint Trial Steering Committee (TSC) and Data Monitoring Committee (DMC) will provide supervision for the trial, providing advice to the Chief and Co-investigators on all aspects of the trial conduct and affording protection for patients by ensuring the trial is conducted according to the Medical Research Council (MRC) Guidelines for Good Clinical Practice in Clinical Trials. The TSC/DMC will be chaired by an academic clinician independent of the trial plus three other members plus the chief investigator, trial manager, statistician, and health economist.

Composition of the data monitoring committee, its role and reporting structure {21a}

Refer to above {5d}

Adverse event reporting and harms {22}

Participants will be monitored throughout the period of the intervention to detect any unintended events.

Frequency and plans for auditing trial conduct {23}

Clinical trial auditing is the primary contact between the sponsor and investigator. In the clinical trial, the sponsor will appoint a few clinical auditors with professional medical or pharmaceutical backgrounds. The auditors must follow the standard operating procedures for clinical research; visit the research unit regularly or according to the ground reality; audit the progress and progress of clinical trials; and check and confirm that the records and reports of all the data and case report forms are correct, complete and consistent with the original data. To ensure that the clinical trial is conducted according to the clinical trial scheme, the researcher will actively cooperate with the auditors. The auditor must be responsible for the below:

Confirm (before the test) that the test undertaking unit has appropriate conditions including personnel allocation and training; ensure that the laboratory is fully equipped and operational; and has various inspection conditions related to the test. They must estimate if there are sufficient subjects and participating researchers are familiar with the test scheme’s requirements.
Monitor (during the experiment) the researcher's implementation of the experimental scheme, confirm that the informed consent of all subjects was obtained (before the experiment), understand the enrollment rate of subjects and progress of the experiment, and confirm that the selected subjects are qualified.
Confirm that all data records and reports are correct and complete, and all case report forms are filled correctly and consistent with the original data. They must also ensure that all errors and omissions are corrected, noted, signed, and dated by the investigator. Dose or treatment changes, combined medication, intermittent diseases, loss of follow-up, examination omission, etc. of each subject must be confirmed and recorded. Furthermore, they must ensure that the withdrawal and loss of follow-up of the selected subjects have been explained in the case report form.
Confirm that all adverse events are recorded, and serious adverse events are reported and recorded within the specified time. They must verify that the intervention products for the test are supplied, stored, distributed, and recovered in accordance with relevant laws and regulations, and make corresponding records.
Assist the researcher in the necessary notification and application processes and report the test data and results to the sponsor.
Clearly and truthfully record the follow-up, test, and inspection that the researcher fails to perform, and document whether the errors and omissions were corrected.
Complete a written audit report (after each visit) which states the date and time of the audit, name of the supervisor, findings of the audit, etc.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

In this trial, if it is necessary, the sponsor and the main researcher can organize the amendments of the protocol. The amended protocol can take effect only after it is signed and aligned by the sponsor and the main researcher and approved by the ethics committee.

Dissemination plans {31a}

We plan to publish one scientific paper in peer- reviewed journals based on the trial and to disseminate the results to patient organizations and the public through printed and electronic media. The outcome of this trial will be reported and presented at national and international conference.

This trial is designed to investigate the efficacy of oral NMN to treat chronic insomnia compared to placebo. To our knowledge, this is the first trial that has a stringent design with randomization and double blinding to investigate evidence targeting chronic insomnia by intaking NMN supplements. The COVID-19 pandemic could pose a challenge to this trial by impacting the inclusion and follow-up of patients. To guarantee patient safety and reduce the risk of COVID-19 infection and spread, we will fully utilize digital platforms such as WeChat and telephone and limit in-person visits.

Chronic insomnia is a prevalent condition associated with significant morbidity, reduced productivity, increased risk of accidents, and poor quality of life. The current first-line treatment is burdensome to some patients. If the hypothesis is verified (i.e., NMN is relatively safe and more effective than placebo), it may be recommended to fulfil the unmet medical needs of patients with chronic insomnia.

The strengths of this trial are:

The use of a randomization scheme with allocation concealment and double blinding.
The use of a placebo similar in appearance and taste to the treatment.
A comprehensive assessment for sleep efficiency.

Trial status

This is protocol version 1, 2 Aug 2021.

Recruitment started on 1 April 2022, with an anticipated primary completion date of 31 Dec 2022.

MNM: Nicotinamide Mononucleotide; SIRT1: sirtuin1; NAD+: sentinel metabolite nicotinamide adenine dinucleotide; CBTI: cognitive behavioral therapy for insomnia; NR: nicotinamide riboside; ICSD: international classification of sleep disorders; ECG: Electrocardiograph; CONSORT: Consolidated Standards of Reporting Trials; CRF: Case report form; CTU: Clinical trials unit; DMC: Data monitoring committee; PSQI: Pittsburgh Sleep Quality Index; ESS: Epworth Sleeping Scale; ISI: Epworth Sleeping Scale; FINS: Fasting serum insulin; AST: Aspartate transaminase; ALT: Alanine transaminase; RCT: Randomized controlled trial; SD: Standard deviation; LOCF: last observation carry forward; TSC: Trial Steering Committee; DMC: Data Monitoring Committee.

Acknowledgements

The authors want to thank all the participants for cooperating and supporting the study

Authors’ contributions {31b}

XYG, JHL, SPX, XYL, XCW, YLL, SHL, HY and ZQ all contributed to the trial design and securing trial funding. XYG, JHL, SPX, and ZQ are involved in the recruitment, the intervention, and the follow-up. XYG will perform data collection and management. XYL, XCW will be responsible for the statistical analysis All authors read and approved the final manuscript.

Funding {4}

This study was supported by the National Natural Science Foundation of China (81872920) and China Health Promotion Foundation (CHPF-Sleeping01).

Availability of data and materials {29}

The datasets generated and/or analyzed during the study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate {24}

Ethical approval was provided by The Medical Ethics Committee of Union Hospital Tongji Medical College Huazhong University of Science and Technology ( ID [2021]（0821）). Informed consent will be obtained prior to trial participation.

Consent for publication {32}

The informed consent form is available from the corresponding author on request.

Competing interests {28}

The authors declare that they have no competing interests.

Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications[J]. Chest, 2014, 146(5):1387-1394.
Avidan AY and DN Neubauer. Chronic Insomnia Disorder[J]. Continuum (Minneap Minn), 2017, 23(4, Sleep Neurology):1064-1092.
Buysse DJ. Insomnia[J]. JAMA, 2013, 309(7):706-16.
Cao XL, SB Wang, BL Zhong, et al. The prevalence of insomnia in the general population in China: A meta-analysis[J]. PLoS One, 2017, 12(2):e0170772.
Chinese Society of Neurology SDS, Chinese Society of Neurology. Guideline for the evaluation and treatment of insomnia in Chinese adults(2017)[J]. Chin J Neurol, 2018, 51(5):324-35.
Miner B, TM Gill, HK Yaggi, et al. Insomnia in Community-Living Persons with Advanced Age[J]. J Am Geriatr Soc, 2018, 66(8):1592-1597.
Wickwire EM, FT Shaya, and SM Scharf. Health economics of insomnia treatments: The return on investment for a good night's sleep[J]. Sleep Med Rev, 2016, 30:72-82.
Khachatryan SG. Insomnia Burden and Future Perspectives[J]. Sleep Med Clin, 2021, 16(3):513-521.
Morgenthaler T, M Kramer, C Alessi, et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An american academy of sleep medicine report[J]. Sleep, 2006, 29(11):1415-9.
Hassinger AB, N Bletnisky, R Dudekula, et al. Selecting a pharmacotherapy regimen for patients with chronic insomnia[J]. Expert Opin Pharmacother, 2020, 21(9):1035-1043.
Cheung JMY, DJ Bartlett, CL Armour, et al. To Drug or Not to Drug: A Qualitative Study of Patients' Decision-Making Processes for Managing Insomnia[J]. Behav Sleep Med, 2018, 16(1):1-26.
Buysse DJ, A Germain, DE Moul, et al. Efficacy of brief behavioral treatment for chronic insomnia in older adults[J]. Arch Intern Med, 2011, 171(10):887-95.
Asarnow LD and R Manber. Cognitive Behavioral Therapy for Insomnia in Depression[J]. Sleep Med Clin, 2019, 14(2):177-184.
Trauer JM, MY Qian, JS Doyle, et al. Cognitive Behavioral Therapy for Chronic Insomnia: A Systematic Review and Meta-analysis[J]. Ann Intern Med, 2015, 163(3):191-204.
van Straten A, T van der Zweerde, A Kleiboer, et al. Cognitive and behavioral therapies in the treatment of insomnia: A meta-analysis[J]. Sleep Med Rev, 2018, 38:3-16.
Dopheide JA. Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy[J]. Am J Manag Care, 2020, 26(4 Suppl):S76-S84.
Buysse DJ, CF Reynolds, 3rd, TH Monk, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research[J]. Psychiatry Res, 1989, 28(2):193-213.
Levine DC, H Hong, BJ Weidemann, et al. NAD(+) Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging[J]. Mol Cell, 2020, 78(5):835-849 e7.
Chang HC and L Guarente. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging[J]. Cell, 2013, 153(7):1448-60.
Nakahata Y, S Sahar, G Astarita, et al. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1[J]. Science, 2009, 324(5927):654-7.
Asher G, D Gatfield, M Stratmann, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation[J]. Cell, 2008, 134(2):317-28.
Camacho-Pereira J, MG Tarrago, CCS Chini, et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism[J]. Cell Metab, 2016, 23(6):1127-1139.
Imai S and L Guarente. NAD+ and sirtuins in aging and disease[J]. Trends Cell Biol, 2014, 24(8):464-71.
Satoh A, CS Brace, N Rensing, et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH[J]. Cell Metab, 2013, 18(3):416-30.
Mehmel M, N Jovanovic, and U Spitz. Nicotinamide Riboside-The Current State of Research and Therapeutic Uses[J]. Nutrients, 2020, 12(6).
Hong W, F Mo, Z Zhang, et al. Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism[J]. Front Cell Dev Biol, 2020, 8:246.
Uddin GM, NA Youngson, BM Doyle, et al. Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise[J]. Sci Rep, 2017, 7(1):15063.
Klimova N, A Fearnow, A Long, et al. NAD(+) precursor modulates post-ischemic mitochondrial fragmentation and reactive oxygen species generation via SIRT3 dependent mechanisms[J]. Exp Neurol, 2020, 325:113144.
Lundt S, N Zhang, X Wang, et al. The effect of NAMPT deletion in projection neurons on the function and structure of neuromuscular junction (NMJ) in mice[J]. Sci Rep, 2020, 10(1):99.
Yoshino M, J Yoshino, BD Kayser, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women[J]. Science, 2021, 372(6547):1224-1229.
Irie J, E Inagaki, M Fujita, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men[J]. Endocr J, 2020, 67(2):153-160.
Mollayeva T, P Thurairajah, K Burton, et al. The Pittsburgh sleep quality index as a screening tool for sleep dysfunction in clinical and non-clinical samples: A systematic review and meta-analysis[J]. Sleep Med Rev, 2016, 25:52-73.
Fabbri M, A Beracci, M Martoni, et al. Measuring Subjective Sleep Quality: A Review[J]. Int J Environ Res Public Health, 2021, 18(3).
Morin CM, G Belleville, L Belanger, et al. The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response[J]. Sleep, 2011, 34(5):601-8.

Table 2 is available in the Supplementary Files section.

Table2.docx

Download PDF

Journal Publication

published 18 May, 2023

Read the published version in Trials →

Reviewers agreed at journal
04 Sep, 2022
Reviewers invited by journal
03 Sep, 2022
Editor assigned by journal
04 Aug, 2022
First submitted to journal
22 Jul, 2022

You are reading this latest preprint version

Oral Nicotinamide Mononucleotide (NMN) to treat chronic insomnia: Protocol for the multicenter, randomized, double-blinded, placebo-controlled trial.

Status:

Journal Publication

Version 1

Abstract

Figures

Administrative Information

Introduction

Background and rationale {6a}

Insomnia

Methods: Participants, Interventions, And Outcomes

Discussion

Abbreviations

Declarations

References

Table 2

Supplementary Files

Status:

Journal Publication

Version 1