Clinical trial NCT02654314
Conditions: Delirium
Keywords: prevention; delirium; in-patients; melatonin,
Sponsor: Yale University
Start date: 2016-07-01; Completion date: 2017-11-03
Enrollment: 277 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A double blind randomized controlled trial investigating melatonin, 5mg, compared to placebo, given to patients at least 65 years old, admitted to the hospital on a general medical floor, to prevent delirium.

Detailed description:
This study will be a randomized double blind controlled trial, designed to evaluate the efficacy of melatonin in decreasing the incidence of delirium in elderly hospitalized adults compared to a placebo capsule. The study will be conducted on 4 general Internal Medicine inpatient floors at Yale-New Haven Hospital, St. Raphael's campus.

Within 24 hours of admission to the floor, study subjects will be approached by a member of the research team, and asked for informed consent. Patients that consent to participate will be randomized to either the treatment or the placebo arm. Each subject will be administered a capsule containing either placebo or 5 mg melatonin each evening at 9 p.m. The capsules will be prepared and administered by the Yale-New haven Hospital Investigational Drug Service. The capsules will be administered nightly until discharge or a maximum of 2 weeks, if the hospitalization is prolonged.

Subjects will be assessed twice daily by the floor nurses for evidence of delirium using the Short CAM (Confusion Assessment Method), which is a validated clinical tool for identifying delirium, and the current standard of practice tool for the diagnosis of delirium.

Arms: arm 1: 5 mg Melatonin nightly, beginning within 24 hours of admission arm 2: Blue capsule matching the melatonin arm
Interventions: intervention 1: Melatonin intervention 2: Placebo
Intervention descriptions: intervention 1: 5 mg Melatonin nightly, beginning within 24 hours of admission intervention 2: Blue capsule matching the melatonin arm

Protocol documents:
Prot_SAP_000.pdf: 
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YALE UNIVERSITY
                                  HUMAN INVESTIGATION COMMITTEE
                                     Application to Involve Human Subjects in Biomedical Research
100 FR1 (2015-2) 
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: Prevention Of Delirium in Inpatients Utilizing Melatonin (PODIUM)
Yale HIC Protocol #1601017038
Principal Investigator: Stephen Atlas, M.D.   
Yale Academic Appointment:
Associate Clinical Professor of Medicine 
Department: Internal Medicine, Saint Raphael Campus 
Campus Address: 
1450 Chapel St. New Haven CT 06510
Campus Phone: 203-789-
3103
Fax: 203-789-3222 Pager:   
E-mail: stephen.atlas@ynhh.org
Protocol Correspondent Name & Address (if different than PI):
 
Campus Phone: 
Fax:   
E-mail: 
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone: 
Fax:   
E-mail: 
Business Manager:
Campus Phone :
Fax :  
E-mail
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)            NA
Yale Academic Appointment:
Campus Address: 
Campus Phone: 
Fax:   
Pager:   
E-mail: 


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See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
  Yes  
  No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
  Yes  
  No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form:  http://www.yale.edu/coi/  
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 Yale University PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center/Clinical Trials Office (CTO)      YCCI/Hospital Research Unit (HRU)
 Yale Cancer Center/Smilow
 YCCI/Keck Laboratories
 Yale-New Haven Hospital
 Yale-New Haven Hospital—Saint Raphael Campus               
in-patient
 Cancer Data Repository/Tumor Registry
 Specify Other Yale Location:
b. External Location[s]:
 APT Foundation, Inc.
 Haskins Laboratories


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 Connecticut Mental Health Center
 John B. Pierce Laboratory, Inc.
 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven
  Other Locations, Specify: 
 International Research Site (Specify location(s)):
c. Additional Required Documents (check all that apply):  
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)   
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS  
Approval Date: 
*Radioactive Drug Research Committee (RDRC)  
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)   
Approval Date: 
 Yale University RSC (YU-RSC)
Approval Date:
 Magnetic Resonance Research Center PRC (MRRC-PRC) Approval Date:
 *Nursing Research Committee
Approval Date:
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 
13 months
3. Research Type/Phase: (Check all that apply)
a. Study Type
    Single Center Study
     Multi-Center Study 
Does the Yale PI serve as the PI of the multi-site study? Yes   
No 
   Coordinating Center/Data Management
   Other: 
b. Study Phase  
 N/A
     Pilot  
 Phase I  
 Phase II 
 Phase III 
 Phase IV
     Other (Specify) 


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4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c:
 Clinical Research: Patient-Oriented  
  
 Clinical Research: Outcomes and 
 Clinical Research: Epidemiologic and Behavioral   
                Health Services
 Translational Research #1 (“Bench-to-Bedside”)      
 Interdisciplinary Research
 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study a clinical trial? Yes    
No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry   NCT00873379
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, or contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes  No
7. Will this study have a billable service? A billable service is defined as any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either 
Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The 
service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include 
x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes: 
1. There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects.
 
Yes 
 No


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 If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu
8. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No ___  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform?
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure?
 
c. Will a novel approach using existing equipment be applied?
 
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol
.
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or  mid-level 
practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet 
the criteria, please telephone the Physician Services Department at 203-688-2615. By signing 
this protocol as a PI, you attest that you and any co-investigator who may have patient contact 
has a medical staff appointment and appropriate clinical privileges at YNHH.
SECTION III: FUNDING,
 RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).  
PI 
Title of Grant  
Name of Funding Source   
Funding  
Funding Mechanism






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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC)
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
ATTACHED AS A SEPARATE DOCUMENT
                                        
                           
   Chair Name (PRINT) and Signature        
 Date
As the faculty advisor of this research project, I certify that:
The information provided in this application is complete and accurate.
This project has scientific value and merit and that the student or trainee investigator has the necessary 
resources to complete the project and achieve the aims.
I will train the student investigator in matters of appropriate research compliance, protection of human 
subjects and proper conduct of research.
The research will be performed according to ethical principles and in compliance with all federal, state and 
local laws, as well as institutional regulations and policies regarding the protection of human subjects.
The student investigator will obtain approval for this research study and any subsequent revisions prior to 
initiating the study or revision and will obtain continuing approval prior to the expiration of any approval 
period.
The student investigator will report to the HIC any serious injuries and/or other unanticipated       problems 
involving risk to participants. 
I am in compliance with the requirements set forth by the University and qualify to serve as       the faculty 
advisor of this project. 
I assume all of the roles and responsibilities of a Principal Investigator even though the student may be 
called a PI.
 
January 5, 2016
Stephen Atlas, MD    ______
                                       
_____
       
   
    
   
 
e f PI
t




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Older adults are known to be particularly vulnerable to the occurrence and effects of delirium 
when suffering an acute stress such as a medical illness or a hospitalization.  The incidence 
of delirium in elderly hospitalized patients has been reported as ranging from 11 to 42% in 
general hospitalizations, and 15 to 62% in post-operative patients4,5.
Treatment of the underlying illness is the current mainstay of treatment for delirium.  
Antipsychotic medications are widely used to manage the symptoms of delirium such as 
agitation and hallucinations.  Side effects of these medications include over-sedation, 
prolonged QTc intervals, increased risk of potentially fatal cardiac arrhythmias, and 
extrapyramidal symptoms.  There are currently no medications approved for the prevention 
of delirium in at risk patients.  
Role of melatonin in delirium 
Melatonin is a neurohormone synthesized from tryptophan and secreted by the pineal gland 
in a circadian pattern governed by the light-dark cycle.
6  It is known as an important mediator 
of the sleep-wake cycle.7  Because disturbance of the sleep wake cycle is a core feature of 
delirium, it has been hypothesized that melatonin may play a role in the pathogenesis of 
delirium8,9.
Both serum daytime levels and nocturnal peaks of melatonin have been shown to decrease 
progressively with age.10,11  Additionally, both serum
12 and CSF
13 levels of melatonin have 
been shown to be markedly reduced in patients with Alzheimer’s dementia, compared to 
controls.  Levels of both serum melatonin and its urinary metabolites
14 have been 
demonstrated to differ in patients with delirium as compared to non-delirious controls15,16,17.
4 Fong TG et al.Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol (2009) 5:210—220 
5 Miller MO.  Evaluation and management of dementia in hospitalized older patients. Am Fam Physcian (2008) 
11:1265—1270 
6 Claustrat B, et al. The basic physiology and pathophysiology of melatonin. Sleep Med Reviews (2005) 9:11—24 
7 Brzezinski A. Melatonin in humans. NEJM (1997) 336:186—195 
8 Lewis MC and Barnett SR.  Postoperative delirium: the tryptophan dysregulation model. Med Hypotheses (2004) 
63:402—406 
9 de Jonghe et al. Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia.  Are there 
implications for delirium?  A systematic review. Int J Geriatr Psychiatry (2010) 25:1201—1208  
10 Iguchi H, et al. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin 
Endocrinol Metab (1982) 55:27—29 
11 Magri F, et al. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging 
and in centenarians. J Pineal Res (2004) 36:256—261 
12 Kazuo M et al.Melatonin secretion rhythm disorders in patietns with senile dementia of Alzheimer’s type with 
disturbed sleep-waking. Biol Psych (1999) 45:417—421 
13 Liu RY et al. Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s 
disease, and apolipoprotein E-epsilon 4/4 genotype. J Clin Endocrinol Metab (1999) 84:323—327 
14 Balan S, et al.The relation between the clinical subtypes of delirium and the urinary level of 6-SMT. J 
Neuropsychiatry Clin Neurosci (2003) 15:363—366 
15 Hidetaka S et al. Postoperative delirium and melatonin levels in elderly patients. Am J of Surg (2001) 182:449--
454
16 Yoshitaka S, et al. Perioperative plasma melatonin concentration in postoperative critically ill patients: its 
association with delirium. J Crit Care (2013) 28:236—242 
17 Sun, et al. Research of 24-hour dynamic sleep monitoring and melatonin changes in patients with delirium in 
intensive care unit. Chinese critical care medicine (2014) 10:726-729 


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Melatonin for the prevention of delirium
Multiple case reports suggest that melatonin, given at a dose of 2 or 4 mg nightly is helpful in 
both prevention and management of delirium in both post-operative and non post-operative 
elderly hospitalized adults
18,19,20.  Several observational studies looking at the use of 
melatonin for the prevention of delirium, primarily in the ICU and post-operative settings, 
have supported the use of melatonin in the prevention of delirium.  Ramelteon, a synthetic 
melatonin agonist, has been shown effective for the prevention of delirium in observational 
studies
21,22, 
23 as well as in a randomized control trial
24.
Randomized Controlled Trials Studying Melatonin for Prevention of Delirium 
A review of the literature revealed three randomized controlled trials to date that have looked 
at the use of melatonin for the prevention of delirium in elderly hospitalized patients.  The 
results of these trials are summarized in the table below: 
The trials outlined have yielded inconsistent results.  While the Sultan and Al Aama studies 
both demonstrated decreased incidence of delirium in both medical and surgical patients 
treated with melatonin, the de Jonghe trial did not show a benefit to melatonin in the 
prevention of delirium.  
A meta-analysis published in April, 2015, extracted data from the four studies described 
above, to consider the incidence of delirium in a total of 669 patients given prophylactic 
melatonin.25  Melatonin was shown to decrease the incidence of delirium, with a RR of 0.41 
(95% CI 0.15—1.13, p=0.08).  In a subgroup analysis that looked at the elderly patients on 
medical (not surgical) services, use of prophylactic melatonin was shown to decrease the 
incidence of delirium by 75%, with a RR of 0.25 (95% CI 0.07—0.88, p=0.03), although no 
statistical difference was found in patients admitted to surgical service.  A major limiting 
factor is the heterogeneity between these studies that looked at different patient populations, 
different doses, and used different scales to assess delirium.  While the collective data is 
intriguing, further study is necessary in order to clarify the potential role of melatonin in the 
prevention of delirium in elderly hospitalized adults. 
18 Hanania M, Kitain E. Melatonin for the treatment of and prevention of postoperative delirium. Anesth Analg 
(2002) 94:338—339 
19 Lammers M, Ahmed AI.  Melatonin for sundown dyndrome and delirium in dementia: is it effective? J Am Geriatr 
Soc (2013) 61:1045—1046 
20 Panagiotis A, et al. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients. 
Polish J of Thoracic and Cardiovascular Surgery  (2015) 12:126—133 
21 Motohide F et al. Marked improvement in delirium with ramelteon: five case reports. Psychogeriatrics (2012) 
12:259--262
22 Akihiro T et al. Ramelteon for the treatment of delirium in elderly patients: a consecutive case series study Int J 
Psych in Medicine (2014) 47:97—104 
23 Ohta T, et al.Melatonin receptor agonists for treating delirium in elderly patients with acute stroke.  J Stroke 
Cerebrovasc Dis. (2013) 22:1107—1110 
24 Hatta K et al. Preventive effects of ramelteon on delirium; a randomized placebo controlled trial. JAMA 
Psychiatry (2014) 71:397—403 
25 Chen S, et al. Exogenous melatonin for delirium prevention: a meta-analysis of randomized controlled trials. Mol 
Neurobiol (2015) 


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Notes 
Results 
Exclusion 
criteria 
Intervention
Definition of 
delirium 
Setting 
Lead 
author/year 
-AMT initially designed to detect cognitive 
impairment, not delirium 
N=222
Control group—32.65% post-op delirium
Melatonin group—9.43% post-op delirium
(p=0.003)
(44% in Versed group, 37.25 in clonidine group)
Hx EtOH abuse
Sensory impairment
Dementia 
Severe anemia or infection
IC event
Fluid/lyte disturbance
Acute cards or pulm event
On anticonvulsants, antidepressants, antihistamines, 
antiparkinsonian agents, antipsychotics, or benzos 
Group 1—no premedication
Group 2—5 mg melatonin nightly, + 5 mg 90 min 
prior to operation
Group 3—7.5 mg Versed nightly and 90 min prior to 
operation
Group 4—100 mg clonidine nightly and 90 min prior 
to operation
AMT (abbreviated mental test) < 8
Post-op patients > 64, following hip arthroplasty 
Sultan, 201026
(single center double blinded RCT)
No statistically significant difference in 
delirium as measured by MDAS
N=122
12% of pts in treatment group developed 
delirium, compared to 31% in placebo 
group 
Expected stay/life expectancy < 48 hours
Non-English speaking
Unable to take oral meds
Hx IC bleed or seizure
Hx non-therapeutic INR on Coumadin
Allergy to melatonin
Group 1—0.5 mg melatonin qHS
Group 2—placebo 
Intervention continued until DC, death, 
or 14 days 
CAM (confusion assessment method)
(delirium as defined by Memorial 
Delirium Assessment Scale was a 
secondary outcome)
Pts > 64, admitted to IP internal med 
service 
Al-Aama, 201127
(Single center double blinded RCT)
-melatonin group had statistically 
shorter duration of delirium 
-had 3 mo follow up to assess cognitive 
function and mortality rates (no 
difference) 
N=378 
29.6% of patients in melatonin group 
developed delirium v 25.5 in the 
placebo group 
Delirium at time of enrolment 
Transfer from OSH 
Already on melatonin
Unable to speak Dutch 
Group 1—3 mg melatonin q HS
Group 2—placebo 
Treatment continued x 5 days 
DSM IV; Delirium observation 
screening scale was completed per each 
nursing shift 
Patients > 64 admitted for acute hip 
surgery  
de Jonghe, 201428
(multicenter, double-blinded RCT)
26 Sultan SS, et al. Assessment of the role of perioperative melatonin in prevention and treatment of postoperative 
delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth (2010) 4:169—173 
27 Al-Aama T, et al. Melatonin decrease delirium in elderly patients: a randomized placebo-controlled trial. Int J 
Geriatr Psychiatry (2011) 26:687—694 
28 de Jonghe, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, 
double-blind randomized controlled trial. CMAJ (2014) 186:547—556 


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3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and 
include any flowcharts of visits specifying their individual times and lengths. Describe 
the setting in which the research will take place.
This study will be a randomized controlled trial, designed to evaluate the efficacy of 
melatonin in decreasing the incidence of delirium in elderly hospitalized adults.  The study 
will be conducted on four  general Internal Medicine inpatient services at Yale-New Haven 
Hospital, St. Raphael’s campus, Verdi 4 West, Verdi 5  North, Celantano 4, and Celantano 3. 
Randomization will be accomplished with the assistance of the Yale Investigative Drug 
Service Pharmacy. They will be using a randomization generator with active/placebo on a 1 
to 1 basis in randomly permutated blocks of 4
Within 24 hours of admission to the inpatient floor, study subjects will be approached by a 
member of the research team, and asked for informed consent.  Patients that consent to 
participate and meet our inclusion criteria will be ordered the appropriate study drug by the 
floor pharmacist, per the Yale Investigative Drug Service’s randomization to either the 
treatment or the placebo arm.  Each subject will be ordered  a capsule containing either 
placebo (cellulose microcrystylline) or 5 mg melatonin each evening at 9 p.m.  The study 
drug can be given as early as 7pm on the day of admission, if necessary,  to allow treatment 
to begin within 24 hours of admission to the floor.. The capsules will be prepared and 
administered by the Yale-New haven Hospital Investigational Drug Service. The capsules 
will be administered nightly until discharge or a maximum of 2 weeks if the hospitalization is 
prolonged. The capsule must be swallowed whole and not opened.
Subjects will be assessed twice daily, once in the- a.m. and again in the p.m by the floor 
nurses for evidence of delirium using the Short CAM (Confusion Assessment Method), 
which is a validated clinical tool for identifying delirium, and the current standard of practice 
tool for the diagnosis of delirium. This evaluation should take maximally 5 to 10 minutes to 
complete. 
While it is considered standard of care for nurses to administer the Short CAM once daily at 
Yale-New Haven Hospital, the twice daily Short CAM is standard of care at the University of 
Connecticut Hospital but not currently at the Yale-New Haven Health System with the 
exception of Verdi 4 West where the CAM is administered twice a day for all patients.
The primary endpoint will be the occurrence of delirium as defined by the Short CAM by the 
time of discharge or prior to hospital day 15, whichever occurs first. The study drug will be 
continued until the primary end point of delirium is reached, discharge or hospital day 15.  
The maximum period of study drug administration will be 14 days. If the patient’s length of 
stay exceeds 14 days the patient’s participation in the study will end and the subject will be 
recorded as having completed the study without delirium.  If the primary end point of 
delirium is reached, the subject will have completed the study, participation will be over and 
the study drug will no longer be administrated.


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While causes of delirium will be extracted from the chart, all investigations will be done by 
the primary inpatient team.  The diagnosis of delirium will be communicated to the inpatient 
team.
Patients that agree to participate in the study will not be prescribed melatonin as a sleeping 
aid.  All care, including medications for sleep and management of delirium will be per 
standard of care, as decided by the attending physician of record.  If the primary team 
believes that melatonin is medically indicated the patient will not be enrolled or be 
withdrawn from the study.
4. Genetic Testing   N/A 
A. Describe
i. the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned
ii.the plan for the collection of material or the conditions under which material will 
be received
iii.the types of information about the donor/individual contributors that will be 
entered into a database
iv.the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
C.Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
i. How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials 
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
The study will recruit subjects > age 65, who are admitted to the four participating general 
internal medicine floors at St. Raphael’s hospital.
6.Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.


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 Children
 Healthy 
Fetal material, placenta, or dead fetus
 Non-English Speaking  
 Prisoners  
 Economically disadvantaged persons
 Decisionally Impaired    Employees   
 Pregnant women and/or fetuses
 Yale Students 
Females of childbearing potential
If patients are not competent to sign the informed consent, we will contact the healthcare proxy 
to provide informed consent for enrollment.
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects?  Yes   No (If yes, see Instructions section VII #4 for further 
requirements)
7.Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion?
Inclusion Criteria
Age > 65
Inpatient admission to general internal medicine service
Exclusion Criteria
Expected lifespan or length of stay < 48 hours
Non-English speaking
Already taking melatonin at the time of randomization (at least one dose taken in the 
prior week)
Already taking ramelteon (Rozerem) at the time of randomization (at least one dose 
taken in the prior week)
Presence of delirium at the time of randomization 
Unable to take oral medications
Subject or proxy unable to provide informed consent 
Unable to give consent within 18 hours of invitation or within 24 hours of being 
admitted to the medical floor
Known allergy to melatonin
Patients taking warfarin, nifedipine and fluvoxamine
Patients with severe liver impairment  (admission diagnosis of active liver disease 
such as cirrhosis or acute hepatitis) 
Unable to recall at least 2 of 3 words after distraction by asking the subject to name 
the days of the week backwards starting with Sunday.
8.How will eligibility be determined, and by whom? 
A member of the research team will use the hospital EMR to screen admissions to the four 
participating general Internal Medicine floors for eligibility, based on the above inclusion 
and exclusion criteria.  This will be accomplished via the OnCore  and YCCI  EPIC Support 
Services.  The consent process will include a brief description of the study with an 


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explanation that the subject may receive no direct benefit from participating but patient care 
may in general improve if the study drug successfully prevents delirium. If the patient is 
interested in enrolling then the patient is asked to remember 3 words (apple, penny, and 
table) and then is distracted by being asked to recite the days of the week backwards starting 
with Sunday. If the subject can remember at least 2 of the 3 words then the entire consent in 
reviewed in depth and the subject is asked if he understands and if he has any questions 
before signing.  A “teach back” will be accomplished to insure that the subject or the 
surrogate understands all the research aspects of the study  A Short CAM will then be 
performed by the investigator to evaluate for delirium.  If  delirium is not diagnosed via the 
Short CAM, the consent form will be completed and the patient entered into the trial.
9.Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
Minimal risks are anticipated with this study however participation in the study may involve 
risks that are currently not know. Possible risks include the swallowing of an extra pill and the 
lack of ability to take melatonin for impaired sleep.  While Micromedex lists 
 side effects of 
melatonin, such as tachyarrhythmia, red/flushed skin, hypothermia, decreased glucose tolerance, 
abdominal cramps/diarrhea, confusion, decreased reaction time, sedation, sleep pattern 
disturbance, and worsening of depression, these are considered rare and usually with little 
clinical effect.  A recent review in the journal Clinical Drug Investigations (Andersen LP, 
Gögenur I, Rosenberg J, Reiter RJ. Clin Drug Investig. 2016 Mar;36(3):169-75. doi: 10.1007/s40261-015-
0368-5. PMID:26692007) concluded that the short-term use of melatonin is safe, even in 
extreme doses and that only mild adverse effects have been reported and are probably no 
different than placebo29, with the possible exception of sleepiness. 
Other potential adverse effects 
include dizziness, headache, and nausea as described below, in section VI.2. 
Melatonin should have no major drug interactions or effects on other possible drug interventions 
in our subjects.  Mild to moderate interactions with warfarin, nifedipine and fluvoxamine are 
noted in Micromedex and patients treated with these medications will not be included in the 
study.
Another possible risk involves potential breach of confidentiality with the collection of 
protected patient information.  All patients in the study will be initially de-identified by use 
of medical record number and subsequently further de-identified by receiving a study 
number.  Paper records will be kept in a locked office and computerized records will be kept 
in a secure hospital computer.
10.Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
Regarding the lack of ability to take melatonin for sleep; this risk is minimal, as melatonin is 
rarely used as a sleeping aid on the participating services.  Currently only 7.2% of patients 
admitted to Celantano 3 and 12.3% of patients admitted to V4 West receive melatonin for 


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sleep. Clinicians will continue to treat insomnia with the usual non-pharmacologic and 
pharmacologic methods.  
All patient data will be logged in a password protected YCCI / OnCore grid that will only be 
accessed by study personnel.  All participants in the study will be HIPAA and HSPT trained.
The investigation team will review all patients, in EPIC or in persontwice per day.  Any 
possible complications will be followed closely.
11.Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a. What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
There is minimal risk anticipated for subjects participating in this study.  Melatonin is 
considered a safe, over-the-counter, non-prescription supplement.  A recent review
29 
concluded that “Melatonin is safe for short-term use, even when given in extreme 
doses. Mild adverse effects, such as dizziness, headache, nausea and sleepiness have 
been reported in levels corresponding to placebo treatments.”  Section 9 lists 
Micromedex’s side effect profile.
b.If children are involved, what is the investigator’s assessment of the overall risk level 
for the children participating in this study? 
Not applicable
c.Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
   
       available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
The principal investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency on a 
monthly basis.  During the review process the principal investigator will evaluate 
whether the study should continue unchanged, require modification/amendment, 
or close to enrollment.
The principal investigator or the Institutional Review Board (IRB) have the 
authority to stop or suspend the study or require modifications.
This protocol presents minimal risks to the subjects and adverse events or other 
problems are not anticipated. In the unlikely event that such events occur, 
Reportable Adverse Events (which are events that are serious or life-threatening 
and unanticipated (or anticipated but occurring with a greater frequency than 
expected) and possibly, probably, or definitely related) or unanticipated problems 
involving risks to subjects or others will be reported in writing within 48 hours to 


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the IRB (using the appropriate forms from the website) and any appropriate 
funding and regulatory agencies. The investigator will apprise fellow investigators 
and study personnel of all adverse events that occur during the conduct of this 
research project through regular study meetings.  
d. For multi-site studies for which the Yale PI serves as the lead investigator:
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
12.Statistical Considerations: Describe the statistical analyses that support the study design. 
13.
Primary Outcome:                                                                                                                                                               
Incidence of delirium per admission of medical geriatric patients                                                                                                                 
Incidence of delirium per patient days of hospitalization in medical admission of geriatric patients
Secondary outcomes:                                                                                                                                                                
Risk factors associated with incident delirium                                                                                                                                               
Duration of delirium by study group                                                                                                                                                            
Hospital length of stay
Sample size based was estimated using openepi.com (similar results with Stata version 14 sample size calculator) 
based on control group incidence of delirium in medical subgroup of 30%.  (Chen et al: Exogenous melatonin for 
delirium prevention: a meta-analysis of randomized controlled trials - Molecular Neurobiology online publication 21 
July 2015) with relative risk reduction of 30 %.
Sample Size:X-Sectional, Cohort, & Randomized Clinical Trials
Two-sided significance level(1-alpha):
95
Power(1-beta, % chance of detecting):
80
Ratio of sample size, Unexposed/Exposed:   
1
Percent of Unexposed with Outcome:
30
Percent of Exposed with Outcome:
21
Risk/Prevalence Ratio:
0.7
Risk/Prevalence difference:
-9
Sample size estimation by the Fleiss method  yielded a total sample size of 734 with 367 in each group.
Descriptive statistics such as percentages for binary categorical variables, means and standard deviations for 
continuous variables. Fisher’s exact test or chi-square test will be used to compare categorical variables. For 
continuous variables we will use t-test of unequal variances for means for normally distributed variables and the 
Wilcoxon-Mann-Whitney where normal distribution cannot be assumed. Risk ratio will be calculated using Stata 
statistical program version 14. (StataCorp LP, 4905 Lakeway Drive, College Station, Texas)  Associations with 
covariates will be tested using logistic regression with presence of incident delirium as the dependent variable.  


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Person days to delirium will be compared between the two groups using Survival analysis with Kaplan Meier 
curves, logrank test and Cox proportional hazards (covariates include age, comorbidities,  medication numbers, 
presence of risk factors for delirium – polypharmacy,  use of psychotropic or sedating medications, and use of 
bladder catheters).
Upon completing enrollment and analysis of 367 subjects,  Dr. Donna Windish, a independent statistical expert, will 
analyze the data.  In addition, an independent geriatrician expert in delirium  will review any equivocal CAM results 
and make a decision as to the occurance of delirium.
SECTION VI: RESEARCH INVOLVING DRUGS,
 BIOLOGICS,
 RADIOTRACERS,
 PLACEBOS AND 
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A.  DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s) 
biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been granted and for 
what indication(s). 
Melatonin—FDA categorized as a dietary supplement for sleep aid
All protocols which utilize a drug, biologic or radiotracer not approved by, but regulated by, the FDA, 
or a radiotracer regulated by the RDRC, must provide the following information:  
a. What is the Investigational New Drug (IND) number assigned by the FDA? 
FDA IND 129224-Melatonin
b. Who holds the IND? 
Dr. Stephen Atlas 
c. All protocols which utilize a radiotracer not approved by, but regulated by the FDA must 
provide the IND number: _______________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.     
Alternatively, an exemption from IND filing requirements may be sought for a clinical
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and
 an exemption is being sought, review the following categories and complete the category that applies
 (and delete the inapplicable categories):


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Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be
exempt from IND regulations if all of the following are yes:
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support
     of a new indication for use or to be used to support any other significant change in the labeling for
     the drug.   Yes   No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and
      the intention of the investigation is NOT to support a significant change in the advertising for the
      product.  Yes   No
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)   
      associated with the use of the drug product.  Yes   No
iv.The investigation will be conducted in compliance with the requirements for institutional (HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56).  Yes   No
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.  Yes   No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or
more of the following (check all that apply):
 Blood grouping serum
 Reagent red blood cells 
 Anti-human globulin
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the
diagnosis made by another, medically established, diagnostic product or procedure; and
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60
Exempt Category 4
  A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND.
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 


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influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
Melatonin is categorized by the FDA as a dietary supplement and is currently in use over the 
counter and ordered in a small percentage of hospitalized patients as a sleep aid.  Side effects of 
melatonin are rare and mild; documented adverse effects to melatonin include dizziness, headache, 
nausea, and sleepiness. With the exception of sleepiness these are similar in incidence to placebo. 
The half-life of melatonin is 30 to 50 minutes. There have been no studies to date that have 
documented any serious adverse effects related to short or even long term use of melatonin.29  
Melatonin is taken orally.  Because it is categorized as a dietary supplement and not a drug, it is 
marketed over the counter, and there is no recommended dose.  It is marketed in doses ranging 
from 0.5 to 10 mg.  See section 9, Risks, for all the possible side effects as listed in Micromedex.
3. Source: a) Identify the source of the drug or biologic to be used. 
The Yale Investigational Drug Service Pharmacy
b) Is the drug provided free of charge to subjects?  Yes   No
    If yes, by whom?   
Per the Department of Medicine Research Grant funding
3. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity. 
 No special storage or preparation will be required.
Check applicable Investigational Drug Service utilized:
        YNHH IDS                                                                         Yale Cancer Center 
        CMHC Pharmacy                                                            West Haven VA
        PET Center                                                       
    None      
         Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.  
  
4. Use of Placebo:  Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a. Describe the safety and efficacy of other available therapies. If there are no other
available therapies, state this. 
There are currently no approved therapies for the prevention of delirium.
29 Andersen, L. P., Gogenur, I., Rosenberg, J., & Reiter, R. J. (2015). The Safety of 
Melatonin in Humans. Clin Drug Investig. doi: 10.1007/s40261-015-0368-5




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 Posters
 Mass E-mail Solicitation
 Telephone
 Letter
    
 Departmental/Center Website
 Television
 Medical Record Review
 Departmental/Center Research Boards  
 Newspaper
 Departmental/Center Newsletters   
 Web-Based Clinical Trial Registries
  YCCI Recruitment database  
 Clinicaltrials.gov Registry 
(do not send materials to HIC)
 Other (describe): subjects that meet inclusion criteria will be approached by a member of the 
research team upon admission to the hospital and recruited for the study.
3.  Recruitment Procedures: 
a. Describe how potential subjects will be identified.
Utilizing  OnCore and it’s EPIC Support Team, a member of the research team will 
screen the list of admitted patients to the participating services daily to identify all new 
admissions who are appropriate candidates to enter the study.  The electronic chart will 
then be reviewed to determine if the potential subjects meet all eligibility criteria and if 
concern for discharge within 48 hours is an issue then the primary treating team will be 
approached for their prediction/plan.
b. Describe how potential subjects are contacted. 
They will be approached on the medicine floor to which they are admitted by a member 
of the research team  Within 24 hours of admission.
c. Who is recruiting potential subjects? 
All listed member of the research team will be responsible for recruiting potential 
subjects. Additionally, after submitting the appropriate HIPAA and research training 
course documentation and with the individual specific approval of the Human 
Investigation Committee, other recruiters may be trained by the team.
4. Screening Procedures
a. Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office?  Yes   No
b.  If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process. 
HEALTH INFORMATION TO BE COLLECTED:
 
HIPAA identifiers: 
 Names 
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits contains 
more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 20,000 or fewer 
people is changed to 000. 


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  Telephone numbers
 Fax numbers 
 E-mail addresses
 Social Security numbers 
 Medical record numbers
 Health plan beneficiary numbers 
 Account numbers 
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older 
 Certificate/license numbers 
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers 
 Web Universal Resource Locators (URLs) 
 Internet Protocol (IP) address numbers 
 Biometric identifiers, including finger and voice prints 
 Full face photographic images and any comparable images 
 Any other unique identifying numbers, characteristics, or codes 
5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship.
Several members of the research team may be working as either the resident or attending 
physician for the study subjects at the time of data collection.  The Yale Investigational Drug 
Service will be doing the randomization so that all will remain blinded as to the treatment arm 
and the placebo arm.
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment purposes only
☐ For inclusion of non-English speaking subject if short form is being used
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;          The patients’ names who are admitted to      
Celantano 3, Celantano 4, Verdi 5 North, and Verdi 4 West and fit our inclusion 
criteria will be sent to the investigators via OnCore / EPIC.  Before interviewing the 
patient we will need to review our exclusion criteria which can be done both via EPIC 
chart review and with discussion with the primary team.  Once we are comfortable 


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that the patient is a candidate for inclusion we will interview the patient and further 
review the inclusion and exclusion criteria and begin the invitation to consider 
participating in the study.  By reviewing the chart and perhaps interviewing the care 
team we will avoid needlessly bothering some patients and be more efficient in our 
recruitment process.
ii.If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;  In the event that a patient does not understand and/or cannot explain back to the 
investigator seeking informed consent, what the study entails, but does give us his/her 
affirmative assent, we will seek out the LAR, in person or by phone, to obtain a 
surrogate consent.
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accou
nting for disclosures log”, by subject name, purpose, date, recipients, and a description of 
information provided.  Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
 Compound Consent and Authorization form
 HIPAA Research Authorization Form
8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent. 
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making. 
Potential subjects will be approached by a member of the research team within 24 hours of their 
admission to the hospital.  Care will be taken to explain the purpose of this study as well as 
potential risks associated with participation. If the subject wishes to proceed then the full consent 
form will be explained, and the potential subject will have opportunity and time to read the consent 
document on their own.
Given our elderly subject population, we anticipate that a percentage of our subjects will have 
cognitive deficits that will render them unable to provide their own informed consent.  In those 
cases, in addition to requiring the subject’s affirmative assent, the medical decision maker of 
record will be approached for informed consent.  In such cases, the medical decision maker will be 
approached in person, if possible.  If this is not possible, telephone consent witnessed and signed 


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by a member of the medical staff will be obtained..  The consent will be faxed to the surrogate if 
possible. All surrogates who give consent and are available to come to the hospital will be 
reconfirmed with written consent as soon as possible. 
All subjects will be evaluated by the investigative team twice daily as long as they remain in the 
study. If subjects regain their capacity to give consent, such consent will be mandatory to their 
continuing in the study.
Consent must be obtained within 18 hours of the invitation to participate for the subject to be 
entered into the trial.
10.Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed.
During the consent process, subjects will be asked to describe their understanding of the study, and 
given an opportunity to ask questions.  If the investigator concludes that a subject lacks the 
capacity to consent, the medical decision maker of record will be approached for consent after the 
subject gives his/her affirmative assent..
11.Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects. 
The subjects will receive the compound authorization and consent to enter the Melatonin to 
Prevent Delirium Study
that will be reviewed by the study team personnel.  
12.Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use. 
Non-English speaking subjects will not be included in the study
12(a) As a limited alternative to the above requirement, will you use the short form* for 
consenting process if you unexpectedly encounter a non-English speaking individual interested 
in study participation and the translation of the long form is not possible prior to intended 
enrollment? 
YES ☐  NO ☒
(not applicable)
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time 
a subject speaking that language is to be enrolled.


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Several translated short form templates are found on our website at: 
 http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short form 
is not available on our website, then the translated short form needs to be submitted to the IRB 
office for approval via amendment prior to enrolling the subject. Please review the guidance and 
presentation on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above. 
13.Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.  
  Not requesting a consent waiver 
  Requesting a waiver of signed consent (to obtain verbal consent from LAR, if not 
available)
        Requesting a full waiver of consent (to access medical records for recruitment 
purposes)
   
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes   No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes   No
OR
c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context?  Yes   No
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.) (to obtain verbal consent via telephone from the LAR, if not available)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
Yes   No




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a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?   
Medical record number
Date of Admission
hyperactive delirium
hypoactive delirium
Length of stay
Age 
Gender
Primary diagnosis
Secondary diagnosis
Mortality
 Use of rstraints
# prn antipsychotic doses
PRN sleep meds
Placement of foley catheter
Result of daily CAM assessment 
b. How will the research data be collected, recorded and stored? 
Research data will be collected and recorded on a password protected Microsoft Excel 
spreadsheet that will only be accessible to study investigators via OnCore
c.    How will the digital data be stored?  CD   DVD   Flash Drive   Portable Hard   
       Drive   Secured Server   Laptop Computer   Desktop Computer   Other
d.    What methods and procedures will be used to safeguard the confidentiality and security of    
the identifiable study data and the storage media indicated above during and after the subject’s 
participation in the study?
Data will be stored on a password-protected computer only (Yale-New Haven Hospital 
network server accessed by password only via OnCore).  All data will be coded and a 
masterlist linking the subject identifiers to the coded research data will be kept in a locked 
location in the hospital, separate from the research data.  
Do all portable devices contain encryption software?   Yes    N/A—portable devices will 
not be used to collect data
         If no, see http://hipaa.yale.edu/guidance/policy.html
 
e. What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured.




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None 
3. Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the 
study that will be provided at no cost to subjects.     
None 
4. In Case of Injury: This section is required for any research involving more than minimal 
risk.
No more than minimal risk is involved.
a.     Will medical treatment be available if research-related injury occurs? 
Yes, during the same hospitalization period.
c. Where and from whom may treatment be obtained? 
From the medical team caring for the patient during the admission.
d. Are there any limits to the treatment being provided? 
We do not expect so, but will defer to the primary medical team caring for the patient.
e. Who will pay for this treatment? 
The patient’s insurance company, or the patient.
f. How will the medical treatment be accessed by subjects? 
The medical treatment will be available during the hospitalization, and the PI will notify 
the primary medical team, as appropriate.