Clinical trial NCT06843187: Lemborexant for the Treatment of Residual Insomnia in Major Depressive Disorder (MDD)
Official title: Lemborexant for the Treatment of Residual Insomnia in Adequately Treated Major Depressive Disorder: a Pilot Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Major Depressive Disorder(MDD)
Insomnia Comorbid to Psychiatric Disorder
Keywords: Lemborexant
Residual Insomnia
Major depressive disorder (MDD)
Ecological momentary assessments (EMA)
Wearable devices
Remote measurement-based care
Randomized controlled trial
Digital health monitoring
Feasibility trial
Pilot study
Placebo-controlled
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
Collaborators: name: University of Toronto
name: Centre for Addiction and Mental Health
name: Toronto Metropolitan University
First posted: 2025-02-24
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A double-blind, randomized placebo-controlled pilot trial will be conducted with 30 adults with MDD and residual insomnia. Participants will be randomized to one of two intervention arms (2:1 allocation): lemborexant (experimental group; n = 20) or placebo (control group; n = 10). There will be a 3-week baseline period prior to the 6-week intervention period (lemborexant or a placebo pill for 2 weeks at 5 mg then 4 weeks at 10 mg) and 4-week follow-up period with weekly clinical assessments. Participants will complete a daily digital sleep diary and frequent EMAs on a web-based survey platform as well as passive digital health monitoring via a wearable device. Semi-structured exit interviews will be completed at the end of the study.
Primary purpose: OTHER

Brief summary: The goal of this clinical trial is to learn if Lemborexant works to treat residual insomnia in adults with depression that is being treated. It will also learn about how practical, tolerable, and effective Lemborexant is. The main questions it aims to answer are:

* Does Lemborexant help participants improve sleep and reduce insomnia symptoms?
* How practical is it to use Lemborexant (how many participants join, drop out, and follow the study rules)? How do participants feel about using it (based on surveys and interviews)?

Researchers will compare Lemborexant to a placebo (a look-alike substance that contains no drug) to see if Lemborexant works to treat residual insomnia in adequately treated major depressive disorder.

Participants will:

* Take Lemborexant or a placebo every day for 6 weeks (2 weeks at 5 mg then 4 weeks at 10 mg)
* Complete clinical assessments and in-person study visits
* Maintain a digital sleep diary and complete daily and weekly self-report ecological momentary assessments (EMAs)
* Use a wearable device which will be used to collect and monitor physiological data

Detailed description: Major Depressive Disorder (MDD) is often accompanied by persistent residual insomnia which does not resolve, even after adequate MDD treatment. Lemborexant is an orexin receptor antagonist involved in the regulation of sleep-wake cycles with a favourable safety profile compared to other sleep medications. There are currently no trials evaluating the feasibility and clinical efficacy of Lemborexant as a treatment for residual insomnia in patients with adequately treated MDD. This pilot study will investigate the feasibility, tolerability, and efficacy of Lemborexant in adults with adequately-treated MDD and residual insomnia.

Eligibility criteria: Inclusion Criteria:

1. Aged 18 to 70 (inclusive), with a self-reported body mass index (BMI) between 19 and 35 kg/m2 (inclusive).
2. Meet criteria for MDD without psychotic symptoms as defined by the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and currently in a MDE as confirmed by the MINI International Neuropsychiatric Interview (MINI).
3. Have not failed more than 2 trials of antidepressant treatments in the current MDE, and have a history of adequate response (clinical outcome rating score of 1 or 2) to at least 1 antidepressant treatment during the current MDE as determined by the Antidepressant Treatment History Form-Short Form (ATHF-SF).
4. Are outpatients.
5. Did not take non-psychotropic or non-central nervous system (CNS) medications suspected to affect sleep-wake function for at least 4 weeks before starting the study.
6. At screening visit 1, self-reported subjective total sleep time (sTST) ≤ 6.5 hours, subjective sleep onset latency (sSOL) ≥ 30 mins, and subjective wake time after sleep onset (sWASO) ≥ 45 mins per night at least three times per week 1 month prior to screening.
7. At screening visit 1, self-reported regular time spent in bed, either sleeping or trying to sleep must be between 7 and 10 hours, inclusive.
8. At screening visit 1, self-reported regular bedtime (i.e., the time the participant gets in bed) between 21:00 and 01:00 and regular wake time (i.e., the time participant wakes and does not go back to sleep) between 05:00 and 10:00.
9. At screening visit 2, confirmation of current insomnia symptoms as determined from responses on the Sleep Diary completed on at least 7 consecutive mornings (minimum 5 of 7 for eligibility), such that sSOL ≥ 30 mins on at least 3 of the 7 nights and/or sWASO ≥ 45 mins on at least 3 of the 7 nights.
10. At screening visit 2, confirmation of sufficient duration of time spent in bed, as determined from responses on the Sleep Diary on the 7 most recent mornings before the visit, such that there are no more than 2 nights with time spent in bed of duration \< 7 hours or \> 10 hours.
11. At screening visit 2, confirmation of regular bedtime (i.e., the time the participant gets in bed) between 21:00 and 01:00 on at least 5 of the 7 preceding nights, and regular wake time (i.e., the time the participant wakes and does not go back to sleep) between 05:00 and 10:00 on at least 5 of the 7 preceding nights.
12. Are able to understand and comply with the requirements of the study, as judged by the investigator(s).
13. Provide written informed consent before initiation of any study-related procedures.
14. Own a smartphone and have reliable access to the internet and a browser on which to complete questionnaires.

Exclusion Criteria:

1. Previously participated in any clinical trial of lemborexant.
2. Have any known sensitivity to lemborexant or their excipients.
3. Failed treatment with an appropriate dose or adequate duration of dual orexin receptor antagonist drugs (efficacy or safety), in the opinion of the investigator.
4. Women who are pregnant or lactating (documented by a positive beta-human chorionic gonadotropin \[beta-hCG\] or human chorionic gonadotropin \[hCG\] urine test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG or hCG).
5. Women who are not using any of the following approved and effective method of contraception or family planning during the study: Combined estrogen- and progestogen-containing hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion and litigation, vasectomized partner, sexual abstinence, or two forms of contraception with any barrier method or oral hormones (e.g., condom plus diaphragm, condom or diaphragm plus spermicide, oral hormonal contraceptives plus spermicide or condom).
6. If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions or the therapeutic focus 4 weeks before screening and the entire duration of participation.
7. Unable to keep any current psychiatric medications unchanged for 4 weeks before screening and for the entire duration of participation in the study.
8. Have active suicidal intent as determined by a score of 3 (severe suicidality with a clear plan and/or intent) or 4 (very severe: suicidal attempts) on item #3 on the HAM-D-17.
9. Have had a course of electroconvulsive therapy or intravenous ketamine therapy in the current episode or any previous episode.
10. According to medical history, have had insomnia associated with another sleep disorder or have a history of any condition that impacted or was likely to impact sleep, including any lifetime diagnosis of sleep-related breathing disorder, periodic limb movement disorder, restless legs syndrome, nightmare disorder, sleep terror disorder, sleepwalking disorder, rapid eye movement (REM) behaviour disorder, or narcolepsy.
11. Exclusionary score on screening instruments to rule out individuals with symptoms of certain sleep disorders other than insomnia: Snoring, Tiredness, Observed Apnea, High Blood Pressure, BMI, Age, Neck circumference, and Gender (STOP-Bang) scores ≥ 5; International Restless Legs Scale (IRLS) scores ≥ 16, Epworth Sleepiness Scale (ESS) \> 15.
12. Habitual naps during the day more than 3 times/week.
13. Transmeridian travel across more than 3 time zones in the 2 weeks before screening, or between screening and study baseline, or plans to travel across more than 3 time zones during the study.
14. Used any modality of treatment for insomnia, including cognitive-behavioural therapy or cannabis within 2 weeks before screening.
15. Excessive caffeine use that in the opinion of the investigator contributes to the participant's insomnia, or habitually consumes caffeine-containing beverages after 18:00.
16. Reports habitually consuming more than 14 drinks containing alcohol per week (females) or more than 21 drinks containing alcohol per week (males).
17. Used prohibited prescriptions or over-the-counter concomitant medications, or used any medication or sleep aid with known effects on sleep within 2 weeks before screening.
18. Comorbid nocturia that is causing or exacerbating the insomnia.
19. Report a history of sleep-related violent behaviour, or sleep driving, or any other complex sleep-related behaviour (e.g., making phone calls, preparing and eating food).
20. Report symptoms potentially related to narcolepsy that in the clinical opinion of the investigator indicates the need for a diagnostic referral for the presence of narcolepsy.
21. For participants who underwent polysomnography (PSG) within the previous year before informed consent:

    1. Age 18-64 years old, inclusive: Apnea Hypopnea Index ≥ 10, or Periodic Limb Movement with Arousal Index ≥ 10.
    2. Age ≥ 65 years old: Apnea Hypopnea Index \> 15, or Periodic Limb Movement with Arousal Index \> 15.
22. Diagnosis of substance dependence or abuse within the last 3 months as determined by MINI.
23. Lifetime history of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms as determined by MINI.
24. Have a MINI diagnosis of obsessive-compulsive disorder, post-traumatic stress disorder (current), assessed by a study investigator to be primary and causing greater impairment than MDD.
25. Have a diagnosis of any personality disorder that is assessed by a study investigator to be primary and causing greater impairment than MDD.
26. Have a concomitant major unstable medical illness, cardiac pacemaker, or implanted medication pump.
27. Have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of seizure except a febrile seizure of infancy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes.
28. A history of risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or the use of concomitant medications that prolonged the QTcF interval.
29. Scheduled for major surgery during the study.
30. Have a clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina).
31. Have uncorrected hypothyroidism or hyperthyroidism. Subjects needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 30 days prior to enrolment.
32. Have any other condition that, in the opinion of the investigator(s), would adversely affect the subject's ability to complete the study or its measures.
33. Justifications for any exclusions based on race, gender, or ethnicity: Non-English-speaking individuals are excluded because the ability to communicate study information, answer questions accurately and completely about the study, and obtain consent are necessary.

Primary outcomes:
measure: Feasibility Outcomes
timeFrame: 13 weeks
measure: Tolerability Outcomes
timeFrame: 10 weeks
Secondary outcomes:
measure: Preliminary Clinical Parameters
timeFrame: 6 weeks
measure: Within-person Correlations
timeFrame: 10 weeks
measure: Standard Deviation
timeFrame: 13 weeks
measure: Change in Physiological Biometrics (Oura Ring Metrics)
timeFrame: 13 weeks
measure: Patient Health Questionnaire-9 (PHQ-9)
timeFrame: 13 weeks
measure: Insomnia Severity Index (ISI-7)
timeFrame: 13 weeks
measure: Generalized Anxiety Disorder-7 (GAD-7)
timeFrame: 13 weeks
measure: World Health Organization Well-being Index (WHO-5)
timeFrame: 13 weeks
measure: Montgomery-Åsberg Depression Rating Scale (MADRS)
timeFrame: 13 weeks
Other outcomes:
measure: Patient Perspectives
timeFrame: 13 weeks
Locations:
city: Toronto
country: Canada
facility: St. Michael's Hospital, Unity Health Toronto
state: Ontario
Study officials:
affiliation: Unity Health Toronto
name: Venkat Bhat, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Manual (on) Transcription: Transcription Conventions, Software Guides and Practical Hints for Qualitative Researchers. 3. Engl. Ed., January 2015. Marburg: dr. dresing et pehl GmbH; 2015.
citation: Wilson EB. Probable Inference, the Law of Succession, and Statistical Inference. J Am Stat Assoc. 1927;22: 209-212. doi:10.1080/01621459.1927.10502953
citation: Topp CW, Ostergaard SD, Sondergaard S, Bech P. The WHO-5 Well-Being Index: a systematic review of the literature. Psychother Psychosom. 2015;84(3):167-76. doi: 10.1159/000376585. Epub 2015 Mar 28.
citation: Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006 May 22;166(10):1092-7. doi: 10.1001/archinte.166.10.1092.
citation: Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA. 1999 Nov 10;282(18):1737-44. doi: 10.1001/jama.282.18.1737.
citation: Bang H, Flaherty SP, Kolahi J, Park J. Blinding assessment in clinical trials: A review of statistical methods and a proposal of blinding assessment protocol. Clin Res Regul Aff. 2010;27: 42-51. doi:10.3109/10601331003777444
citation: Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.
citation: Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57.
citation: HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56-62. doi: 10.1136/jnnp.23.1.56. No abstract available.
citation: Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001 Jul;2(4):297-307. doi: 10.1016/s1389-9457(00)00065-4.
citation: Edward KL, Garvey L, Aziz Rahman M. Wearable activity trackers and health awareness: Nursing implications. Int J Nurs Sci. 2020 Mar 25;7(2):179-183. doi: 10.1016/j.ijnss.2020.03.006. eCollection 2020 Apr 10.
citation: Lee S, Kim H, Park MJ, Jeon HJ. Current Advances in Wearable Devices and Their Sensors in Patients With Depression. Front Psychiatry. 2021 Jun 17;12:672347. doi: 10.3389/fpsyt.2021.672347. eCollection 2021.
citation: Ahmed A, Aziz S, Alzubaidi M, Schneider J, Irshaidat S, Abu Serhan H, Abd-Alrazaq AA, Solaiman B, Househ M. Wearable devices for anxiety & depression: A scoping review. Comput Methods Programs Biomed Update. 2023;3:100095. doi: 10.1016/j.cmpbup.2023.100095. Epub 2023 Jan 30.
citation: Martin J, Rueda A, Lee GH, Tassone VK, Park H, Ivanov M, Darnell BC, Beavers L, Campbell DM, Nguyen B, Torres A, Jung H, Lou W, Nazarov A, Ashbaugh A, Kapralos B, Litz B, Jetly R, Dubrowski A, Strudwick G, Krishnan S, Bhat V. Digital Interventions to Understand and Mitigate Stress Response: Protocol for Process and Content Evaluation of a Cohort Study. JMIR Res Protoc. 2024 May 6;13:e54180. doi: 10.2196/54180.
citation: Eisai Inc. PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION: DAYVIGO Lemborexant Tablet Tablet, 5 mg, 10 mg, Oral. 2023.
citation: Uzun S, Kozumplik O, Jakovljevic M, Sedic B. Side effects of treatment with benzodiazepines. Psychiatr Danub. 2010 Mar;22(1):90-3.
citation: Yardley J, Karppa M, Inoue Y, Pinner K, Perdomo C, Ishikawa K, Filippov G, Kubota N, Moline M. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial. Sleep Med. 2021 Apr;80:333-342. doi: 10.1016/j.sleep.2021.01.048. Epub 2021 Feb 1.
citation: Eisai Inc. U.S. FDA APPROVES EISAI'S DAYVIGOTM (LEMBOREXANT) FOR TREATMENT OF INSOMNIA IN ADULT PATIENTS. 2019. Available: https://www.eisai.com/news/2019/news201993.html#:~:text=IN%20ADULT%20PATIENTS-,U.S.%20FDA%20APPROVES%20EISAI'S%20DAYVIGO%E2%84%A2%20(LEMBOREXANT)%20FOR%20TREATMENT%20OF,OF%20MORE%20THAN%202%2C000%20PATIENTS
citation: Regulatory Decision Summary for Dayvigo. Government of Canada; 2024. Available: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS00757
citation: Nakamura M, Nagamine T. Neuroendocrine, Autonomic, and Metabolic Responses to an Orexin Antagonist, Suvorexant, in Psychiatric Patients with Insomnia. Innov Clin Neurosci. 2017 Apr 1;14(3-4):30-37. eCollection 2017 Mar-Apr.
citation: Kuriyama A, Tabata H. Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis. Sleep Med Rev. 2017 Oct;35:1-7. doi: 10.1016/j.smrv.2016.09.004. Epub 2016 Oct 28.
citation: Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, Walsh JK, Krystal AD, Benca RM, Cohn M, Lines C, Roth T, Herring WJ. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 May;13(5):461-71. doi: 10.1016/S1474-4422(14)70053-5. Epub 2014 Mar 27.
citation: Triantafillou S, Saeb S, Lattie EG, Mohr DC, Kording KP. Relationship Between Sleep Quality and Mood: Ecological Momentary Assessment Study. JMIR Ment Health. 2019 Mar 27;6(3):e12613. doi: 10.2196/12613.
citation: Fortuyn HA, Lappenschaar MA, Furer JW, Hodiamont PP, Rijnders CA, Renier WO, Buitelaar JK, Overeem S. Anxiety and mood disorders in narcolepsy: a case-control study. Gen Hosp Psychiatry. 2010 Jan-Feb;32(1):49-56. doi: 10.1016/j.genhosppsych.2009.08.007. Epub 2009 Oct 1.
citation: Grafe LA, Bhatnagar S. Orexins and stress. Front Neuroendocrinol. 2018 Oct;51:132-145. doi: 10.1016/j.yfrne.2018.06.003. Epub 2018 Jun 19.
citation: Salomon RM, Ripley B, Kennedy JS, Johnson B, Schmidt D, Zeitzer JM, Nishino S, Mignot E. Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry. 2003 Jul 15;54(2):96-104. doi: 10.1016/s0006-3223(02)01740-7.
citation: Schmidt FM, Brugel M, Kratzsch J, Strauss M, Sander C, Baum P, Thiery J, Hegerl U, Schonknecht P. Cerebrospinal fluid hypocretin-1 (orexin A) levels in mania compared to unipolar depression and healthy controls. Neurosci Lett. 2010 Oct 8;483(1):20-2. doi: 10.1016/j.neulet.2010.07.038. Epub 2010 Jul 22.
citation: Brundin L, Bjorkqvist M, Petersen A, Traskman-Bendz L. Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. Eur Neuropsychopharmacol. 2007 Sep;17(9):573-9. doi: 10.1016/j.euroneuro.2007.01.005. Epub 2007 Mar 7.
citation: Nollet M, Leman S. Role of orexin in the pathophysiology of depression: potential for pharmacological intervention. CNS Drugs. 2013 Jun;27(6):411-22. doi: 10.1007/s40263-013-0064-z.
citation: Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S. Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology. 2012 Sep;37(10):2210-21. doi: 10.1038/npp.2012.70. Epub 2012 Jun 20.
citation: Nollet M, Gaillard P, Minier F, Tanti A, Belzung C, Leman S. Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression. Neuropharmacology. 2011 Jul-Aug;61(1-2):336-46. doi: 10.1016/j.neuropharm.2011.04.022. Epub 2011 Apr 23.
citation: Scammell TE. Narcolepsy. N Engl J Med. 2015 Dec 31;373(27):2654-62. doi: 10.1056/NEJMra1500587. No abstract available.
citation: Yoshida Y, Fujiki N, Nakajima T, Ripley B, Matsumura H, Yoneda H, Mignot E, Nishino S. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities. Eur J Neurosci. 2001 Oct;14(7):1075-81. doi: 10.1046/j.0953-816x.2001.01725.x.
citation: Pae CU, Tharwani H, Marks DM, Masand PS, Patkar AA. Atypical depression: a comprehensive review. CNS Drugs. 2009 Dec;23(12):1023-37. doi: 10.2165/11310990-000000000-00000.
citation: Alijanpour S, Khakpai F, Ebrahimi-Ghiri M, Zarrindast MR. Co-administration of the low dose of orexin and nitrergic antagonists induces an antidepressant-like effect in mice. Biomed Pharmacother. 2019 Jan;109:589-594. doi: 10.1016/j.biopha.2018.10.033. Epub 2018 Nov 3.
citation: Berridge CW, Espana RA. Hypocretins: waking, arousal, or action? Neuron. 2005 Jun 2;46(5):696-8. doi: 10.1016/j.neuron.2005.05.016.
citation: Nutt D, Wilson S, Paterson L. Sleep disorders as core symptoms of depression. Dialogues Clin Neurosci. 2008;10(3):329-36. doi: 10.31887/DCNS.2008.10.3/dnutt.
citation: Shariq AS, Rosenblat JD, Alageel A, Mansur RB, Rong C, Ho RC, Ragguett RM, Pan Z, Brietzke E, McIntyre RS. Evaluating the role of orexins in the pathophysiology and treatment of depression: A comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8;92:1-7. doi: 10.1016/j.pnpbp.2018.12.008. Epub 2018 Dec 18.
citation: Health Quality Ontario. Psychotherapy for Major Depressive Disorder and Generalized Anxiety Disorder: A Health Technology Assessment. Ont Health Technol Assess Ser. 2017 Nov 13;17(15):1-167. eCollection 2017.