Conditions: Delirium Delirium, Dementia, Amnestic, Cognitive Disorders Delayed Emergence From Anesthesia Cognitive Disorders
Keywords: Post-operative Delirium
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
This trial focuses on a Phase II randomized masked clinical trial testing the effectiveness and safety of peri-operative administration of ramelteon, a melatonin agonist in the prevention of postoperative delirium.

Detailed description:
This trial will randomize older aged patients undergoing general or regional anesthesia for orthopedic surgical procedures to three perioperative doses of a melatonin agonist, ramelteon, and placebo in a masked double blind fashion. The primary outcomes are 1) the incidence of post-operative delirium in the recovery period in the Postoperative Anesthesia Care Unit and on post-operative days 1 and 2 following surgery, and 2) the safety of ramelteon as documented by the presence of adverse events in the follow-up period.

Arms:
arm 1: Ramelteon 8 mg oral dose Riboflavin 100 mg (preoperative first dose only) arm 2: Capsule Shells filled with microcrystalline cellulose Riboflavin 100 mg (preoperative first dose only - if received as an outpatient)

Interventions: intervention 1: Ramelteon intervention 2: Microcrystalline Cellulose intervention 3: Riboflavin 100 mg
Intervention descriptions: intervention 1: 1 pre-operative and 2 nightly postoperative doses of Ramelteon/placebo will be administered intervention 2: Placebo Comparator intervention 3: Riboflavin will be added to both placebo and active intervention capsules in order to track adherence to dose while taken as an outpatient (i.e. only the first preoperative dose)

Protocol document:
Prot_SAP_000.pdf: 
 
 
A Randomized Double Blind Placebo 
Controlled Trial of Ramelteon in the 
Prevention of Postoperative Delirium in 
Older Patients Undergoing Orthopedic 
Surgery: The RECOVER Study 
R21 AG050850-01A1 
 
NCT02324153 
 
Study Protocol and Statistical Plan  
 
Date of Last IRB Approval: 7/12/19 
Johns Hopkins University School of 
Medicine 
Karin J. Neufeld MD MPH 
 
 
 
 
 
 
 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
1JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 1 of 20 
 
RECOVER STUDY Protocol 
 
1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research. 
 
Postoperative delirium, an acute confusional state caused by an underlying physiological 
disturbance following surgery and characterized by sleep/wake cycle disturbances, 1is a serious 
public health problem that disproportionately affects older people. 2,3Delirium is associated with 
many negative outcomes including: increased mortality, longer hospital stays, increased 
institutionalization after acute care hospitalization, worse cognitive and physical outcomes (both 
short- and long-term), and significant distress for patients and their families. 4-9Costs to the 
healthcare system due to all episodes of delirium among the elderly range from $38 to $152 
billion/year. 10,11Aging of the population means increasing numbers of older adults are undergoing 
surgery – making postoperative delirium prevention an urgent priority. 12  
The mechanisms leading to postoperative delirium are unclear, though delirium is almost always 
accompanied by symptoms of sleep-wake disturbance, such as daytime somnolence and nighttime 
sleeplessness. 13-16 Diurnal dysregulation may be causally important in the genesis of delirium, and 
melatonin agonists may prevent delirium by maintaining the circadian rhythm. 17 The rationale for 
using a melatonin agonist is further strengthened by multiple biological effects on neuro-
inflammatory mechanisms implicated in delirium, 18-20via antioxidant and possibly anti-amyloid 
effects. 21-23 Reports from a recent single-blind randomized controlled trial (RCT) of ramelteon in a 
related but non-generalizable older-aged medically ill patient population suggest a significant 
reduction in new onset delirium (30% of placebo-treated vs. 3% of ramelteon-treated; effect size of 
0.85). 24  
We propose a proof-of-concept (phase 2) double-blind randomized placebo-controlled trial to 
evaluate the efficacy and short-term safety of ramelteon for the prevention of postoperative delirium 
in a high-risk group of patients, 65 years and older, with MMSE25 scores > 15, planned orthopedic 
surgery. Our prior work demonstrates the feasibility of conducting a prevention trial in this 
population, using state-of-the-art delirium detection and diagnosis methodology. 5,25 Should this 
preliminary trial, show evidence of efficacy and adequate safety, then a phase 3 trial will be 
proposed.  
Our group has demonstrated that an early predictor of subsequent delirium is the presence of 
delirium immediately upon recovery from general anesthesia in the post anesthesia care unit 
(PACU). 5,26,27The proposed trial will incorporate assessment of PACU delirium as a means of early 
delirium detection in helping to determine the efficacy of the ramelteon intervention.  
 
2. 
Objectives (include all primary and secondary objectives) The proposed trial will involve 
administering 8 mg ramelteon orally (1 dose preoperatively and 2 doses postoperatively) or 
placebo in 80 older-aged patients to test the following: 
 
Specific Aim 1 (primary outcome): To compare delirium incidence and severity between 
ramelteon and placebo using the DSM 5 criteria by expert panel consensus.  
Hypothesis 1: Compared to placebo, ramelteon will be associated with a) a lower incidence and 
severity of postoperative delirium immediately upon recovery from anesthesia in the PACU, and b) 
with a lower incidence and severity of delirium on postoperative day (POD) 1 and POD 2.  


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
2JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 2 of 20 
 
Specific Aim 2 (safety outcome): To compare adverse events (AEs) and serious adverse events 
(SAEs) between ramelteon and placebo.  
Hypothesis 2: Ramelteon will have an adequate safety profile in this postoperative cohort, 
sufficient to support conducting a larger prevention trial. Specifically, compared to placebo, 
ramelteon will not be associated with increased incidence of postoperative delirium or with 
increased adverse side effects including fatigue, headache and next day somnolence during the 
treatment episode.  
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research) 
 
a. Significance: 
 a.1. Overview: Postoperative delirium in older adults is frequent, associated with poor outcomes, 
and a serious public health problem. Delirium, or an acute confusional state caused by an 
underlying physiological disturbance, 1 occurs in up to 60% of older patients undergoing major 
surgery.12,  27-30 It is associated with increased mortality, morbidity, cognitive impairment, 
functional decline, institutionalization following acute care hospitalization, and psychological 
distress for patients and their families.5-9  Healthcare costs due to all episodes of delirium in the 
elderly range from $38 to $152 billion/year.10,11  Older age and impaired cognition prior to surgery 
are risk factors for postoperative delirium. 31,32 For many older patients, a postoperative delirium 
can tip the balance and result in significant reductions in independence and function. 33  
 
a.2. Delirium: A syndrome characterized by a circadian rhythm disturbance. Disrupted sleep-
wake cycle occurs in 73-80% of patients with delirium and includes day/night reversal and 
fragmentation.14,16 Motor activity during a delirious episode is also frequently inappropriate in its 
timing – with daytime somnolence and nighttime hyperactivity, suggesting circadian dysfunction 
as a possible central mechanism in delirium.13,15  The relationship may be bidirectional: sleep 
deprivation may lead to significant cognitive deficits and may itself cause or worsen delirium. 
13,34,35 Sleep/wake cycle disruption is central to postoperative delirium.  
 
a.3. Melatonin: A critical modulator of circadian rhythm that decreases with age. Melatonin 
is secreted by the pineal gland in response to the suprachiasmatic nucleus (SCN) in the 
hypothalamus, which contains a free running circadian pacemaker and is also entrained by neural 
input from the retina where photoreceptors are stimulated by darkness and inhibited by light. 
Noradrenergic photoreceptors synapse in the SCN, stimulating fibers that travel to the superior 
cervical ganglion and return to the pineal gland where production of melatonin occurs, from its 
precursor, serotonin. Melatonin levels peak in the evening and night hours with a 24-hour 
periodicity.  36-38 In healthy young adults the daytime/nighttime peak values are 10/60 pg/mL, 
respectively. Melatonin production peaks in young children and falls over the course of the 
lifespan. 37  Serum melatonin levels are significantly lower, with delayed peak values in older 
subjects with insomnia compared to age-matched controls. Older individuals have decreased 
nocturnal pineal melatonin synthesis, thought to be secondary to neurodegeneration. 39 
 
a.4. Melatonin: Additional neuroprotective effects via antioxidant activity at high doses. 
When administered at 10-100 times the physiologic dose (3-30 mg orally), melatonin exerts cell 
protection through antioxidant activities, modulates the immune system, and supports 
mitochondrial function. 21  It acts via cellular membrane G protein-coupled melatonin receptors 
MT1 and MT2 throughout the human brain, including microglia in the cortex and brainstem, and in 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
3JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 3 of 20 
 
the periphery in cell types such as lymphocytes, bone marrow, gut and retina. Receptor stimulation 
enhances antioxidant potential of the cell by increasing enzyme and mitochondrial ATP synthesis. 
40  Animal models have demonstrated the protective effects of melatonin after ischemic and 
reperfusion injury of liver, heart and brain. 41-46 Evidence suggests that melatonin might be a 
rational treatment for cerebral edema due to blood brain barrier protection. 47-49 Melatonin also 
protects against Aβ-mediated toxicity and attenuates Alzheimer-like tau hyperphosphorylation. 22,23  
 
a.5. Pathophysiology of Delirium: Neuroinflammation and neurotransmitter dysregulation are 
implicated as possible mechanisms causing delirium, particularly in response to stress and 
inflammation of surgical procedures and the direct effects of anesthetic agents. 13,50-52 Impaired 
cerebral oxidative metabolism resulting in increased dopaminergic, noradrenergic and 
glutamatergic activity and decreases in cholinergic activity is hypothesized to cause delirium. 
18,19,35,52,53 Melatonin blocks dopamine release from the hypothalamus in animal models.  
Melatonin agonists may have beneficial effects in delirium prevention through: 1) maintenance of 
sleep and diurnal rhythms, 2) anti-inflammatory effects, and/or 3) dopamine blockade.  
 
a.6. Low Postoperative Serum Melatonin: Associated with delirium. Melatonin levels have 
been reported to be low on the first night following surgery, returning to normal in subsequent days 
when measured in young women following gynecologic procedures. 54 Inpatients developing 
delirium after undergoing major abdominal surgery without life-threatening postoperative 
complications had lower serum melatonin levels compared to preoperative baseline; no such 
change was evident in patients who did not develop delirium. 55 Although absolute preoperative 
levels of melatonin were similar in an observational study of older patients undergoing major 
surgery, patients who developed postoperative delirium demonstrated significantly lower serum 
melatonin concentration at 1 hour after surgery compared to those who remained delirium free. 56 
Postoperative delirium, without life-threatening complications, is associated with lower melatonin 
levels immediately following surgical procedures. 
 
a.7. Exogenous Melatonin and Delirium Prevention: findings are mixed. Two trials in 
postoperative patients used superphysiologic doses: the first using 7.5 mg melatonin orally the 
night prior to, and a second dose 90 minutes before surgery.  Active treatment was compared to 
patients receiving two other agents or no drug at all. A placebo was not used. The new occurrence 
of delirium on days 0-3 in the groups with no drug treatment vs. melatonin was 33% vs. 9%, 
respectively. 57 The second was a recently published placebo-controlled RCT, testing oral doses of 
3 mg of melatonin, administered for 5 consecutive nights in 378 older patients (mean age 84 years) 
undergoing hip fracture repair. This trial demonstrated neither delirium preventive effect (55/186 
or 30% among melatonin group vs. 49/192 or 26% in the placebo) nor any functional differences at 
3 months. 58 Secondary analysis revealed that patients treated with melatonin, had fewer episodes 
of delirium lasting longer than 2 days, compared to placebo. 58 Another placebo-controlled RCT 
was conducted in a medically ill patient population aged 65 and older using a physiologic dose of 
0.5 mg of melatonin at bedtime for up to 14 days during a medical hospitalization. 59 The delirium 
prevalence in placebo vs. melatonin (31% vs.12% respectively; p<0.02) resulted in an absolute risk 
reduction of 15.6% (NNT = 6.4).  
 
a.8. Advantages of Ramelteon – include quality control and longer drug effect. Unlike 
melatonin, which is considered a dietary supplement, ramelteon is an FDA-regulated 
pharmaceutical. Inadequate comparability of biologic availability of melatonin, between different 
manufacturers and even between batches from the same company, has been cited as a major barrier 
to studying the effects of exogenous melatonin in clinical trials. 36 As a regulated drug, ramelteon, 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
4JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 4 of 20 
 
has distinct advantages with respect to quality control and comparable melatonergic activity. 
Furthermore a biologically active metabolite M-II contributes to a longer total drug effect of 5 
hours compared to 1- 2 hours for melatonin. 39,60  
 
a.9.Ramelteon and Delirium Prevention: Promising in medically ill patients. A trial employing 
ramelteon in a delirium prevention study of 67 medically ill patients, > 65 years of age 
demonstrated a significant reduction in delirium in ramelteon-treated vs. placebo (3% vs. 32% 
respectively; p = 0.003) reflecting a relative risk (RR) of 0.09 (95% CI 0.01-0.69).24 Of 1,126 
patients screened, 101 met inclusion criteria. Exclusions included a length of hospital stay or life 
expectancy < 48 hours, diagnosis of 1) liver failure, 2) Dementia with Lewy Bodies, 3) alcohol 
dependency, 4) psychotic disorder, 5) bipolar disorder, or 6) prior use of fluvoxamine. Outcome 
measures were DSM –IV  61   based delirium diagnosis and DRS-98R  62 as assessed by study 
psychiatrists. The intervention and control groups were balanced regarding important confounders: 
patients were comparable in baseline demographics, levels of baseline dementia and severity of 
illness. No one stopped the ramelteon due to adverse outcomes.  The most significant risk of bias 
was due to a non-identical appearing placebo, potentially leading to unmasking of treatment 
assignment.  
 
a.10. Summary of Significance: Sleep disruption is a central feature of delirium, and preliminary 
data suggests that melatonin deficiency is associated with postoperative delirium in older adults. 
The use of ramelteon as a melatonin agonist perioperatively could prevent delirium by a number of 
mechanisms including enhancing circadian rhythm and promoting sleep, direct antioxidant and 
anti-inflammatory activity and central dopamine blockade. While results of melatonin RCTs have 
been quite mixed, ramelteon offers pharmacokinetic and pharmacodynamic advantages over 
melatonin that may enhance potential benefits.  Successful prevention of postoperative delirium 
will result in improvements in the lives of older patients undergoing surgery and significant cost-
savings to the healthcare system. 
 
b. Innovation:  
b.1. Melatonergic agents - a safer alternative for delirium prevention: Previous delirium 
prevention trials have tested pharmacologic agents that directly increase cholinergic, or decrease 
dopaminergic activity. Rivastigmine, a cholinesterase inhibitor, was discontinued mid-study due to 
concern for increased mortality in the treatment group. 63 Dopamine-blocking antipsychotic agents 
(i.e. haloperidol) have not demonstrated any treatment or prevention benefit for delirium in 
critically ill adults. 64,65 Results of dopamine blocking agents in prevention trials in older-aged 
postoperative samples are mixed: antipsychotics may hold some promise 66 but are complicated by 
the increased risk of stroke and sudden death, particularly with long-term use in patients with 
dementia, making this a high-risk strategy for the highest risk patients. 67-69 Safer delirium 
pharmacologic prevention strategies are needed. Ramelteon, as a melatonin agonist, may have a 
more benign side-effect profile in older people and is approved currently as a sleep aide. 39,70,71  
 
b.2. A Different High-Risk Population reflecting “real-world” surgical patients: Ramelteon 
has not yet been used as a delirium-prevention agent in a postoperative population which includes 
persons with significant cognitive impairment. Our group has expertise early delirium evaluation 
following recovery from anesthesia on the day of surgery in addition to assessments on 
postoperative days. This first study of ramelteon in an older postoperative patient population 
inclusive of those with preoperative cognitive impairment will use the innovative approach of early 
delirium detection to study the evolution of the syndrome in the immediate recovery period and on 
subsequent postoperative days.  


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
5JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 5 of 20 
 
 
b.3. A Rigorously Conducted RCT Ensuring Adherence: A trial that includes complete 
masking of study drug/placebo and ensures adherence to first dose through testing for a tracer 
substance will represent a unique contribution to scientific knowledge. Rigor is needed to 
demonstrate that delirium prevention effects are due to ramelteon, particularly before designing 
more expensive phase 3 trials. A rigorously conducted RCT will identify the potential for 
ramelteon to prevent delirium in a postoperative population.     
 
b.4. Summary of Innovation: This exploratory study is a novel approach to preventing 
postoperative delirium in older patients with and without cognitive impairment – a condition for 
which there is no prevention and little translational inquiry. Older individuals undergoing surgery, 
do so in the hopes of improving quality of life. Delirium prevention following surgery will 
significantly improve independence, well-being and decrease institutionalization. A widely 
available, generally safe intervention (ramelteon) would be exciting, novel, guiding translational 
inquiry to test important new mechanistic models of postoperative delirium.   
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
Overview: This randomized, masked, controlled trial is designed to evaluate the short-term safety 
and efficacy of peri-operative, orally administered 8 mg of ramelteon for the prevention of 
postoperative delirium; 80 delirium-free participants (n=40 per arm) > 65 years of age, infection 
free and undergoing orthopedic surgery and post-procedure inpatient admission, will be randomized 
to ramelteon/placebo at the preoperative study visit, with administration of 3 nightly doses: one 
preoperatively and two following surgery while monitoring incidence of postoperative delirium. 
The following diagram outlines the proposed study timeline.  All activities outlined in yellow 
indicate research activities while white background indicates routine clinical care.  
 
Timeline of Clinical Course and Study Assessment (not to scale) 
 
 
 
 
 
 
*See Table for  
Assessment  
description. 
 
 
Choice of dosing times: include three consecutive evenings: 1) prior to surgery, 2) the night of 
surgery or POD 0 and 3) POD 1. The preoperative administration of ramelteon is designed to 
correct melatonergic deficiencies observed immediately following surgery and to enhance circadian 
rhythm and sleep effects. 54 Participants who are admitted to hospital the night before surgery will 
have study assigned medication administered by clinical staff, similar to the procedure for POD 0 
and POD 1 doses. Participants undergoing elective surgery are given the first dose of medication at 
their preoperative study visit with instructions to take it the night before surgery. Study personnel 
will contact to remind the participant. Lack of adherence to self-administration of medication has 
been described as a barrier in the literature. 72 Serving as a biologic tracer, 100 mg of riboflavin 
(Vitamin B2) will be added to both the active agent and placebo of doses to be self-administered 
Ramelteon 8 mg/Placebo 
by Mouth the night prior to 
Surgery 
PACU Delirium 
Upon Recovery from Anesthesia 
PACU 
Aldrete Score >8 
Ramelteon 8 mg/Placebo 
by Mouth 
on Evening of Surgery 
Ramelteon 8 mg/Placebo 
by Mouth on Evening 
Postoperative Day 1 
IQCODE, CDR, Functional Assessments 
Baseline Data:  Demographics, Comorbidities, Blood Draw 
Clinical Course 
Study Assessments* 
Delirium POD #1 
Delirium POD #2  
Delirium 
Patient Interview & Medical Record Review for Adverse Events (using “Health Questionnaire”) 
Medication Administration Documentation (adherence to study protocol) Blood Draw POD #1 & 2 
Randomization 
Preoperative Evaluation of 
Consenting Patients 
Urine sample collection testing 
for riboflavin tracer prior to 
surgery 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
6JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 6 of 20 
 
outside of the hospital. Since riboflavin fluoresces under UV light, a urine sample obtained in the 
OR at the time of catheterization, will be sent for quantitative fluoroscopy using a cutoff of > 900 
ng/ml as evidence of adherence. Replacement recruitment will be completed for any participants 
with urine samples negative for riboflavin.   
 
 
Choice of study population and outcome measurement time points: Delirium, diagnosed early in 
recovery from anesthesia, is very common in older adults (45% after recovery from general 
anesthesia) and predicts delirium in the subsequent postoperative course. 5,26,27,73This finding runs 
contrary to the view that postoperative delirium cannot be diagnosed unless a period of lucidity has 
occurred following recovery from anesthesia, and that commonly observed confusion and 
uncooperativeness upon recovery are benign emergence phenomena. 74 Since our previous work 
suggests that the syndrome, regardless of its attribution, predicts delirium in the days 
following surgery as well as measurable changes in cognitive function, 5 we have included two 
time periods of delirium incidence as our primary outcome: 1) in the PACU after recovery of 
arousal, hemodynamic, and respiratory function after anesthesia, as measured by Aldrete score > 
8;74 and 2) during POD 1 and 2 independent of status in the PACU. This will allow for the study of 
preoperative ramelteon on immediate recovery and during the traditionally described delirium 
incidence in the days following surgery. For participants who discharge early from the hospital 
(prior to POD 2), delirium assessment will be conducted via telephone.  While longer-term follow-
up beyond POD 2 is desirable, it is difficult to complete in all patients in this preliminary study due 
to an institutional trend toward early post-surgery discharge. We plan to recruit patients with 
significant cognitive impairment at baseline (mild to moderate dementia) by including participants 
with Mini Mental State Exam (MMSE) scores > 15. 75Based upon our previous work, distribution of 
MMSE scores of 24-30, 15-23, and < 15 prior to surgery for this population will be 50-60%, 25-
33% and 7-25% respectively. Participants who score below this cut-off are increasingly difficult to 
test, making delirium diagnosis difficult. 
 
Randomization: A statistician (JML) will be responsible for design, implementation, and 
maintenance of randomization procedures that assign participants to active pharmaceutical or 
placebo. Since preoperative cognitive impairment is consistently and strongly associated with the 
development of postoperative delirium, our randomization process will stratify by preoperative 
MMSE exam score to ensure balanced allocation (MMSE score 24/30 - 30/30 and 15/30 - 23/30). 
Under supervision of the statistician, research pharmacy staff who have no contact with the patient 
or clinical staff will randomize participants using a computer program, utilizing dynamic allocation 
probabilities to balance the two groups on the dichotomous MMSE variable.   
 
Masking Procedures: The research pharmacy staff will prepare the active treatment (ramelteon 8 
mg) and placebo using identical gel caps containing 100 mg riboflavin for doses to be self-
administered outside of the hospital. No riboflavin will be added to study doses to be administered 
by hospital nursing staff. Once randomized, the assigned agent will be labeled with the patient’s 
name and medical record number with the administration instructions consistent with hospital 
policy. No markings will indicate identity of the agent. Participants admitted on the day of surgery 
will receive the assigned study medication (active treatment/placebo) at the study visit prior to 
surgery. For all inpatient doses clinical nursing staff will administer medication each evening (8-10 
pm). Administration will be documented in the clinical electronic medication record and adherence 
closely monitored by research staff. 
 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
7JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 7 of 20 
 
Concomitant Medications: All medications except those enumerated in exclusions will be 
allowed.60 
 
Choice of Clinical Site and Feasibility of Recruitment: A total of 198 infection-free inpatients > 65 
years of age, underwent total hip or knee arthroplasty or revision under general anesthesia between 
01/01/14-12/31/14 at JHBMC. The median (IQR) ASA physical status score and median surgical 
duration (IQR) was 3 (3-3) and 172 (122-216) mins. respectively, reflecting significant comorbidity 
and lengthy surgical times, consistent with high postoperative delirium risk likely to be at least 
30%. 58 
 
b. Study duration and number of study visits required of research participants.  
 
The study will include baseline data gathering prior to surgery and last for three days during 
admission to hospital for orthopedic surgery.  The participants in this study will be invited to come 
to a hospital-based in-person preoperative study visit to obtain consent for the study, collect 
baseline data, including 5 ml (1 teaspoon) of blood draw for biomarkers and a baseline delirium 
assessment. If the patient is unable or unwilling to come to the hospital prior to surgery, study staff 
will offer to come to see the patient in the community such as in their home (if located within the 
vicinity of JHBMC and the patient is willing).  If the patient lives out of state, or too far to allow 
study team travel, but still expresses interest in the study, the consent will be sent via email (from 
the secure JHMI server) or via fax after discussing the study with one of the provider staff by 
telephone. Baseline information that can be completed by phone will be obtained and remaining 
variables and blood draw will be completed in the morning of the day of surgery. Following 
randomization, study medication will be sent by courier or mail. 
 
The patient will be asked to take the study medication (either ramelteon or placebo - both containing 
riboflavin) the night before surgery.  For many patients this will occur at home prior to admission and 
research personnel will place telephone calls to ensure adherence by the patient. While in the hospital the 
patient will have a urine sample collected and sent on the day of surgery to test for riboflavin, will be 
visited by study staff to do a delirium assessment in the PACU upon recovery from anesthesia, and on two 
subsequent postoperative days. Two doses of the study drug will be prepared by the research pharmacy and 
administered by the patient’s nurse. Blood will be drawn for biomarkers on POD1 and POD2. For the 
biomarker collection on POD1 and POD2, 5 ml (1 teaspoon) of blood will be collected during routine AM 
blood draw, and therefore will not involve an additional needle stick. If the participant is discharged from 
the hospital early (prior to POD2), the biomarker collection for that day will not be completed. For 
participants who are discharged from the hospital on postoperative day 0 or day 1, the remaining doses of 
study medication will be packaged by the pharmacy and given to the participant to take at place of 
discharge with instructions to take the medication at hour of sleep.  Study staff will call the participant and 
complete the study questionnaires each day by telephone should the patient be discharged prior to 
postoperative day 2.  
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Blinding of study staff, clinical staff and the patient is critical for the design and the study aims – 
which seek to test whether ramelteon might prevent the development of postoperative delirium.  
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
8JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 8 of 20 
 
Participants will receive routine surgical and postoperative care.  The study seeks to add exposure to 
ramelteon or placebo to test whether this intervention might decrease delirium - a common 
complication that occurs in the postoperative setting in older adults. No current therapy will be 
stopped.  
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
The inclusion of a placebo treatment is critical in helping advance our understanding of the effects 
(both positive and negative) of ramelteon exposure.  Placebo comparison is the only way that we 
can understand what is likely due to ramelteon and what is not.  
 
f. Definition of treatment failure or participant removal criteria. 
 
All consented participants will be retained in the study.  Participants with no evidence of riboflavin 
in the urine sample as tested by fluorescence prior to surgery (i.e. evidence of non-adherence to the 
first dose of study agent) will continue in the study, receiving second and third doses of study agent, 
and undergoing delirium outcome measures at all time points; however recruitment will continue 
until 80 participants with documented adherence to the first doses of study agent is attained.  
Primary analysis will be intent to treat with all randomized subjects included in the analysis; 
secondary analysis will include only patients with documented adherence all 3 doses of study 
medication (a per protocol analysis). 
 
Participants who have their surgery canceled after they have been randomized and who are likely to 
have surgery in the future will be considered “suspended” from the study.  These participants will 
continue in their assigned condition.  A new baseline will be completed prior to their new surgery 
date to establish that they continue to meet inclusion criteria.  The team will proceed with the 
protocol pre- and postoperatively as assigned during the original randomization. If the participant 
takes any of the study medication prior to the original surgery, a minimum of 7 days between initial 
study dosing and the re-initiation of the protocol is required to ensure sufficient time to wash out. If 
the rescheduled surgery occurs less than 7 days after original dosing, the participant will be 
excluded from the study.  
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Patients will be thanked for their help with the study and will be advised to call the PI with any 
questions.  
 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
9JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 9 of 20 
 
5. 
Inclusion/Exclusion Criteria 
 
Participants and Recruitment: Eligible patients at JHBMC, identified from the surgical scheduling 
roster (after obtaining HIPAA waiver) and/or from referral by the patient’s surgeon will be 
approached. Upon receiving informed consent from the patient or their legally authorized 
representative (LAR), a MMSE 75 and delirium assessment (see below) will determine eligibility. A 
similar recruitment procedure is employed in the ongoing STRIDE study at the JHBMC. Both 
elective and emergency surgeries will be eligible.  Recruitment of ethnic and racial minority 
participants will be a priority.   
 
Inclusion Criteria: 1) Planned orthopedic surgery and inpatient stay following surgery; 2) Age > 65 
years; 3) MMSE > 15 before surgery; 4) Can understand, speak, read and write English. 
 
Exclusion Criteria: 1) Delirium diagnosis by Confusion Assessment Method 76(CAM) at baseline; 
2) Unable to give informed consent (as tested for with the consent questionnaire during telephone 
screening and during baseline visit) due to cognitive impairment and a suitable LAR cannot be 
identified; 3) Declines participation; 4) Current medications that include: a) ramelteon, b) 
melatonin, c) fluvoxamine, d) rifampin, e) ketoconazole, or f) fluconazole; 5) History of ramelteon 
or riboflavin intolerance; 6) Heavy daily alcohol intake by medical record or history 7) Current 
moderate to severe liver failure (as defined by Charlson criteria82); 8) Evidence of Systemic 
Inflammatory Response Syndrome (SIRS) as measured by > 2 criteria; 77 or 9) Presence of a 
condition that in the opinion of the PI might compromise patient safety if enrolled in the study. 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Choice of agent and dose: Ramelteon is fast in onset. In a study of its safety and efficacy in older 
adults with chronic primary insomnia, using a two night crossover double-blind randomized 
controlled design, 8 mg of ramelteon demonstrated statistically significant decreases in sleep 
latency, increased sleep efficiency, and total sleep time compared to placebo as measured by 
polysomnography. 78A ‘first night’ model of transient insomnia in 289 patients, naïve to a sleep 
laboratory environment and without any prior sleep difficulties, demonstrated similar findings with 
exposure to one dose. 71 Increased side effects, including fatigue, headache, and next-day 
somnolence, were experienced with 16 mg vs 8 mg, with no additional sleep architecture benefit. 60 
Ramelteon (8 mg dose) is rapidly absorbed with peak serum concentrations at 1 hour and results in 
20 -30 times the equivalent of nocturnal plasma melatonin levels. Such superphysiologic dosing 
may confer additional melatonergic neuroprotective benefits. Easily absorbed and highly protein 
bound, ramelteon is subject to extensive first pass metabolism, and rapidly eliminated (t1/2 =1-2.6 
hours). However the M II metabolite is highly biologically active, binding to both melatonin and 
serotonin-2B receptors. Elderly individuals metabolize ramelteon less rapidly than younger 
subjects, resulting in a doubling of exposure, given the same dose. 60,79 Use of 8 mg of ramelteon in 
this protocol should confer both sleep promoting and circadian rhythm maintenance, and is a 
sufficient dose to provide superphysiologic melatonin receptor stimulation potentially 
consistent with antioxidant effects at a dose with relatively few side effects.  
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed. 
 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
10JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 10 of 20 
 
An FDA waiver of need for IND was received on January 5th 2015 (see attached letter rejecting 
application for IND).  One of the reasons given by the FDA was that the “investigation does not 
involve a change in route of administration, dosage or population, or other factor that significantly 
increases the risks (or decreases the acceptability of risks) associated with the use of the drug 
product.” 
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  – Not applicable. 
 
7. 
Study Statistics 
a. Primary outcome variables. 
Outcome Measure Specific Aim I – State-of-the-Art Delirium Assessment and Diagnosis: Well-
trained research staff will conduct delirium assessments at baseline, to exclude cases of 
prevalent delirium, and at three later time points (see Figure and Table). This assessment 
includes: (1) face to face standardized interview of the patient regarding experiences, (2) 
standardized cognitive testing including the MMSE 75 and the abbreviated Digit Span, 80(3) 
history from family/friends familiar with the patient’s cognitive baseline, (4) interview of 
nursing and other medical staff caring for the patient, and (5) review of medical records for 
evidence of behavioral disturbances and symptoms in previous 24 hours. Information on sleep 
disturbance is sought from all sources and is a symptom of delirium. Assessors will rate the 
CAM 81 and the Delirium Rating Scale-Revised ’98 (DRS-R98) 62 for the prior 24 hours and 
describe the patient’s behavior and mental state in a written narrative. If a patient is intubated 
the CAM-ICU 82 will be administered to determine delirium status. Patients who are comatose 
will be documented as such. (Preliminary data suggests that this is a rare occurrence <1%) Final 
adjudication of delirium diagnosis is derived after all data is presented to a panel of expert 
delirium diagnosticians (KN, PR and EO).  
 
The primary diagnosis of delirium is based upon meeting all DSM-5 criteria (see 
appendix), and is determined by consensus of the expert panel - a method currently 
employed by this group of co-investigators in the STRIDE study.  
 
A second outcome measure will be analyzed using the continuous variable of delirium 
severity derived from the DRS-98R severity measure.  
 
Outcome Measure Specific Aim II- Adverse Events: All adverse events (AE and SAE) will be collected 
from the medical record and daily patient assessment using a customized instrument (“Health 
Questionnaire”) which will systematically probe for known side effects (fatigue, headache and next day 
somnolence) (see Protection of Human Subjects).Assessment of Outcome and Covariates:  
Table: Timing and Content of Patient Assessments 
Assessments  
Administration 
Collection Instrument and Source 
Cognition  
Preoperative, PACU 
POD 1 and 2 
Mini Mental State Exam 
Abbreviated Digit Span: Forwards and Backwards  
Delirium 
Preoperative, PACU, 
POD 1 and 2 
CAM (full)83 after patient exam + proxy/medical record review or CAM-
ICU if intubated; DRS-98R (severity measure) 
Dementia Rating 
Preoperative 
IQCODE from Proxy Interview; CDR based on Testing and Patient 
Interview 
Age/sex/ race/occupational and 
education 
Preoperative 
Data Collection from based on Chart Review and Patient/Proxy Interview 
Activities of Daily Living (ADL); 
Instrumental ADL  
Preoperative 
Katz and Lawton Scales from Patient and Proxy Interviews; Frailty 
Measure: Modified Fried Criteria 
Comorbidities and review of sleep 
Preoperative/POD 1 and 
Charlson Index from Chart review, ASA score;  


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
11JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 11 of 20 
 
patterns;  
POD 2 
Pittsburgh Sleep Quality Index (baseline); Richards Campbell Sleep 
Questionnaire (POD 1 and 2) 
Blood sample (5 ml) 
Preoperatively, POD 1 
and 2 
Testing for the following inflammatory biomarkers: CRP (all testing will 
be performed by a research laboratory)  
Medication administration (study 
agents), OR record/hospital 
course/discharge 
Preoperative, PACU, 
POD 1 and 2 
Data Collection based on Chart Review  
Adverse events  
PACU, POD 1 and 2 
SAE + AE Custom-made Data Collection Forms (“Health Questionnaire”) 
from Patient Interview and Records 
 
b. Secondary outcome variables. 
 
Baseline Covariate Measures:  
Dementia Assessments: To measure the preoperative cognitive function, 1) patient interview and 
testing and 2) Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) 83 
completed at baseline after interview of a proxy informant, will inform rating of the 6 domains 
of the Clinical Dementia Rating (CDR) 84 by the delirium assessor. Evidence for the CDR 
ratings will be adjudicated by the consensus panel. 
Other Baseline Covariates: Demographics, Activities of Daily Living (ADL’s), 85,86 
Instrumental ADL’s (IADL’s), 87 validated measures of medical comorbidity and severity 
(Charlson Comorbidity Index, 88 and ASA physical status classification system 89), and a 
validated measure of sleep, Pittsburgh Sleep Quality Index (PSQI) 90 will be documented 
preoperatively. The PSQI measures characteristics of nighttime sleep in the prior month: 
producing a score of 0 – 21 (lower = better sleep) with a cut-off of > 5 indicating poor sleep 
quality. Richards Campbell Sleep Questionnaire will be collected from the patient on POD 1 
and POD 2 to document in-hospital quality of sleep. We will also collect the modified Fried 
Frailty Criteria at baseline.   
 
c. Statistical plan including sample size justification and interim data analysis. 
 
Choice of Sample Size; Power Considerations– Why 80 adherent participants? The power to 
detect a difference in the development of postoperative delirium of an the previously reported 
effect-size 24(30% placebo-treated vs. 3% ramelteon-treated) is greater than 0.90, using the 
current design of 40 participants in each treatment arm and assuming 30% of the placebo-treated 
group will develop delirium on POD 1 or 2. This design can detect an 80% reduction in delirium 
(30% placebo-treated vs. 6% ramelteon-treated) with a power of 0.84.  A conservative estimate 
for power for the continuous outcome (DSRS-98R) measuring delirium severity can be derived 
by conceptualizing the proposed longitudinal analysis as an independent samples t-test.  With 
alpha of 0.05 and a sample size of 80, and with means in the ramelteon and placebo groups of 
5.75 and 11.34, respectively (as reported in Hatta, et al), and SDs of 4.16 and 10.96, we would 
have 84% power to detect that difference.   Power for the planned analysis, which includes 3 
post-surgery measurements per participant, and controls for baseline measurement and 
additional covariates would likely be greater. 
 
Data Analysis-Specific Aim 1:  
Analysis 1:Odds of postoperative delirium upon immediate recovery will be modeled via 
logistic regression with treatment assignment as the covariate of interest, and controlling for 
baseline MMSE, surgical duration and sleep disorders in all randomized participants in a strict 
intent to treat model and also in a second analysis among the 80 first-dose adherent 
participants.91 Odds of delirium on POD’s 1 and 2 will be modeled via a Markov logistic 
regression model 92 as a function of treatment assignment, baseline MMSE, and mental status on 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
12JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 12 of 20 
 
the previous day, where two transitions are possible: from normal mental status to delirium 
and/or coma (abnormal mental states) and the reverse.  Correlation of mental status on 
consecutive days for the same individual will be modeled using generalized estimating 
equations (GEE). 92 We will fit models with interactions between treatment group and variables 
hypothesized to predict treatment response, including baseline MMSE and sleep to determine if 
treatment response varies as a function of baseline predictors. 
 
Analysis 2: The continuous DRS-98R severity measure of delirium will be modeled via 
longitudinal linear regression with correlated observations within participants addressed via the 
method of GEE with treatment assignment as the covariate of interest and controlling for 
baseline DRS-98R score, MMSE, surgical duration and sleep disorders.  
 
Data Analysis-Specific Aim 2: Risk of a severe adverse event will be modeled as a function of 
treatment assignment using logistic regression, as will counts of total adverse events using 
ordinal logistic regression or Poisson regression as appropriate.  Counts of each specific type of 
AE, as a function of treatment assignment will be scrutinized to determine the power needed to 
study them in future larger-scale trials. 
 
d. Early stopping rules.  This is a pilot study and will continue until 80 adherent participants are 
recruited.  A Data Safety Monitoring Board will review the data at the end of year one or at 
recruitment of 40 adherent participants (whichever comes first) to review the unblinded 
(labelled “A” and “B”) data for safety of the intervention.  Specifically, for the analyses of rates 
of delirium in the two groups, we will use a Haybittle-Peto boundary such that the alpha for the 
interim analysis will be 0.001, and the alpha for the final efficacy analysis will be 0.05.    
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
Risks associated with the Study Treatment: Ramelteon has FDA approval for use in elderly 
patients with insomnia.  However this agent has never been used peri-operatively in older patients 
undergoing general or regional anesthesia and we cannot be certain that it will be safe in this 
setting.  Therefore the study aims to test safety of this agent compared to placebo; we will 
systematically collect daily information on adverse (AE) and serious adverse events (SAE) that 
occur in each arm of the study. The main potential risk is one of increased incidence of delirium due 
to the treatment intervention.  Other risks associated with the use of ramelteon reported in product 
labeling include:  1) angioedema and anaphylactic reactions – this risk is extremely rare; 2) 
worsening of insomnia, or the emergence of new cognitive or behavioral abnormalities that may be 
the result of an unrecognized underlying psychiatric or physical disorder, such as worsening of 
depression (including suicidal ideation and completed suicides), hallucinations, bizarre behavior, 
agitation and mania; 4) amnesia, anxiety and other neuro-psychiatric symptoms may also occur 
unpredictably, including complex behaviors such as "sleep-driving" (i.e., driving while not fully 
awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, 
making phone calls, or having sex) with amnesia for the event; 5) decreased testosterone levels and 
increased prolactin levels have been reported with long-term use; 7) the use is contraindicated in 
severe hepatic failure as evidenced by cirrhosis, ascites, portal hypertension and prolonged bleeding 
times; 8) also contraindicated with the concomitant use of fluvoxamine; and finally 9) caution is to 
be used when prescribing with other CYP enzyme active agents such as rifampin, fluconazole, and 
ketoconazole. Other less serious side effects that have been reported in clinical trials include 
somnolence, fatigue, dizziness, nausea and worsened insomnia.  


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
13JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 13 of 20 
 
The following is taken from the ramelteon package insert:   
ADVERSE REACTIONS  
The following serious adverse reactions are discussed in greater detail in other sections: Severe 
anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.1)] Abnormal 
thinking, behavior changes, and complex behaviors [see Warnings and Precautions (5.3)] CNS 
effects [see Warnings and Precautions (5.4)]  
6.1 Clinical Trials Experience  
Adverse Reactions Resulting in Discontinuation of Treatment  
The data described in this section reflect exposure to ROZEREM in 5373 subjects, including 722 
exposed for 6 months or longer, and 448 subjects for one year.  
Six percent of the 5373 individual subjects exposed to ROZEREM in clinical studies discontinued 
treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo. The 
most frequent adverse events leading to discontinuation in subjects receiving ROZEREM were 
somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the 
patients or less.  
ROZEREM Most Commonly Observed Adverse Events  
Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic 
insomnia who participated in placebo-controlled trials of ROZEREM.  
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of other 
drugs, and may not reflect the rates observed in practice. The adverse reaction information from 
clinical trials does, however, provide a basis for identifying the adverse events that appear to be 
related to drug use and for approximating rates.  
Table 1. Incidence (% of subjects) of Treatment-Emergent Adverse Events  
  
Term 
 Placebo (n= 1456) 
Ramelteon 8 mg (n=1405) 
Somnolence 
2 % 
3% 
Fatigue 
2% 
3% 
Dizziness 
3% 
4% 
Nausea 
2% 
3% 
Insomnia exacerbated 
2% 
3% 
 
b. Steps taken to minimize the risks. 
We will adhere to the exclusion criteria listed above which will help avoid the recruitment of 
patients most at risk of side effects and adverse consequences. Patients will be interviewed each day 
for any side effects and the medical records will be reviewed and the data collected for Aim 2 of the 
study.  A DSMB will review the data as described above and the study will be halted if there is 
evidence of harm significantly associated with the intervention. We will also inform participants of 
the risks – particularly when taking the first dose at home.  Specifically we will advise them to call 
911 or come to an emergency room if, after taking the study drug, they develop any swelling, rash, 
difficulty or noisy breathing. 
 
The clinical team (Attending Surgeon - eg., Co-Investigators: Khanuja, Sterling, Oni and the Chief 
of Anesthesiology - eg., Co-Investigator Sieber) will be notified by the study team should any 
patient be found to be delirious (thereby ineligible) during the screening process for the study.  The 
Attending Surgeon (or his designee) will be responsible for contacting the patient's family and 
arranging subsequent follow-up of the patient - either in an emergency setting, in the clinic, or 
through early admission to hospital. The precise recommendation will be informed by the clinical 
status of the patient.  


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
14JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 14 of 20 
 
  
c. Plan for reporting unanticipated problems or study deviations. 
 
All AE’s and SAE’s will be reported to the IRB and the DSMB in keeping with rules of the Johns 
Hopkins Institutional Review Board.  As noted above – data on adverse effects will be collected 
each day of the study.   
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
As with any study incorporating research as a part of clinical care, there is a small but real risk of 
unintentional release of HPI.  We will make every effort to secure data and study records under lock 
and key and encryption in keeping with institutional standards to prevent this from occurring.   
 
e. Financial risks to the participants. 
 
The financial risks to the participants related specifically to this protocol are minimal.   
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
While there may be no clear benefit for those participants who take part, this study is an important 
next step in the discovery of pharmaceutical agents in postoperative delirium prevention.  A 
positive outcome may help relieve suffering of many patients in our healthcare system in the 
future and stimulate further inquiry delineating the role of melatonin in the genesis of 
delirium, potentially benefiting society. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. 
 
Participants whose participation requires an extra study visit prior to their surgery will be 
compensated $50. No payment is planned for those who are hospitalized prior to their surgery since 
all study activities will be conducted while they are inpatients. Study medication (including active 
agent – ramelteon or placebo) will be provided and administered free of charge to the patient. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify 
who will pay for them. 
The study budget will include payment for all of the additional procedures (i.e. urine on day 
of surgery, analysis of blood biomarkers at all time points) and drugs – both active and 
placebo, used in this study.   


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
15JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 15 of 20 
 
 References 
1. American Psychiatric Association, American Psychiatric Association. DSM-5 Task Force. Diagnostic and 
statistical manual of mental disorders: DSM-5. 5th ed. Arlington, Va.: American Psychiatric Association; 2013. 
2. Inouye SK. Delirium in older persons. N Engl J Med. 2006 Mar 16; 354(11): 1157-1165. 
3. Jones RN, Fong TG, Metzger E, Tulebaev S, Yang FM, Alsop DC, Marcantonio ER, Cupples LA, Gottlieb G, 
Inouye SK. Aging, brain disease, and reserve: Implications for delirium. Am J Geriatr Psychiatry. 2010 Feb; 18(2): 
117-127. 
4. Fong TG, Jones RN, Marcantonio ER, Tommet D, Gross AL, Habtemariam D, Schmitt E, Yap L, Inouye SK. 
Adverse outcomes after hospitalization and delirium in persons with alzheimer disease. Ann Intern Med. 2012 Jun 
19; 156(12): 848-56, W296. PMCID: PMC3556489. 
5. Neufeld KJ, Leoutsakos JM, Sieber FE, Wanamaker BL, Gibson Chambers JJ, Rao V, Schretlen DJ, Needham 
DM. Outcomes of early delirium diagnosis after general anesthesia in the elderly. Anesth Analg. 2013 Aug; 117(2): 
471-478. PMCID: PMC4017627. 
6. Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients 
and the risk of postdischarge mortality, institutionalization, and dementia: A meta-analysis. JAMA. 2010 Jul 28; 
304(4): 443-451. 
7. Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after 
postoperative delirium. N Engl J Med. 2012; 367: 30-39. 
8. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, 
Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely 
EW. Long-term cognitive impairment after critical illness. N Engl J Med. 2013 10/03; 2013/12; 369(14): 1306-1316. 
9. Davis DH, Muniz Terrera G, Keage H, Rahkonen T, Oinas M, Matthews FE, Cunningham C, Polvikoski T, 
Sulkava R, MacLullich AM, Brayne C. Delirium is a strong risk factor for dementia in the oldest-old: A population-
based cohort study. Brain. 2012 Sep; 135(Pt 9): 2809-2816. PMCID: PMC3437024. 
10. Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers L, Inouye SK. One-year health care costs associated with 
delirium in the elderly population. Arch Intern Med. 2008; 168: 27-32. 
11. Leslie DL, Inouye SK. The importance of delirium: Economic and societal costs. J Am Geriatr Soc. 2011 Nov; 
59 Suppl 2: S241-3. 
12. Robinson TN, Raeburn CD, Tran ZV, Angles EM, Brenner LA, Moss M. Postoperative delirium in the elderly: 
Risk factors and outcomes. Ann Surg. 2009 Jan; 249(1): 173-178. 
13. Fitzgerald JM, Adamis D, Trzepacz PT, O'Regan N, Timmons S, Dunne C, Meagher DJ. Delirium: A disturbance 
of circadian integrity? Med Hypotheses. 2013 Oct; 81(4): 568-576. 
14. Mattoo SK, Grover S, Chakravarty K, Trzepacz PT, Meagher DJ, Gupta N. Symptom profile and etiology of 
delirium in a referral population in northern india: Factor analysis of the DRS-R98. J Neuropsychiatry Clin Neurosci. 
2012 Winter; 24(1): 95-101. 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
16JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 16 of 20 
 
15. Meagher DJ, Moran M, Raju B, Gibbons D, Donnelly S, Saunders J, Trzepacz PT. Motor symptoms in 100 
patients with delirium versus control subjects: Comparison of subtyping methods. Psychosomatics. 2008 Jul-Aug; 
49(4): 300-308. 
16. Meagher DJ, Moran M, Raju B, Gibbons D, Donnelly S, Saunders J, Trzepacz PT. Phenomenology of delirium. 
assessment of 100 adult cases using standardised measures. Br J Psychiatry. 2007 Feb; 190: 135-141. 
17. de Rooij SE, van Munster BC. Melatonin deficiency hypothesis in delirium: A synthesis of current evidence. 
Rejuvenation Res. 2013 Aug; 16(4): 273-278. 
18. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: When cytokines and 
acetylcholine collide. Lancet. 2010 Feb 27; 375(9716): 773-775. 
19. Field RH, Gossen A, Cunningham C. Prior pathology in the basal forebrain cholinergic system predisposes to 
inflammation-induced working memory deficits: Reconciling inflammatory and cholinergic hypotheses of delirium. J 
Neurosci. 2012 May 2; 32(18): 6288-6294. PMCID: PMC3359617. 
20. Cunningham C, Maclullich AM. At the extreme end of the psychoneuroimmunological spectrum: Delirium as a 
maladaptive sickness behaviour response. Brain Behav Immun. 2013 Feb; 28: 1-13. 
21. Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin--a pleiotropic, 
orchestrating regulator molecule. Prog Neurobiol. 2011 Mar; 93(3): 350-384. 
22. Polimeni G, Esposito E, Bevelacqua V, Guarneri C, Cuzzocrea S. Role of melatonin supplementation in 
neurodegenerative disorders. Front Biosci (Landmark Ed). 2014 Jan 1; 19: 429-446. 
23. Lin L, Huang QX, Yang SS, Chu J, Wang JZ, Tian Q. Melatonin in alzheimer's disease. Int J Mol Sci. 2013 Jul 
12; 14(7): 14575-14593. PMCID: PMC3742260. 
24. Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, Nakamura H, for the DELIRIA-J Group. Preventive 
effects of ramelteon on delirium: A randomized placebo-controlled trial. JAMA Psychiatry. 2014 Feb 19. 
25. Neufeld KJ, Leoutsakos JS, Sieber FE, Joshi D, Wanamaker BL, Rios-Robles J, Needham DM. Evaluation of 
two delirium screening tools for detecting post-operative delirium in the elderly  <br />  <br />   <br />. Br J Anaesth. 
2013 May 8; 111(4): 612-618. 
26. Sharma PT, Sieber FE, Zakriya KJ, Pauldine RW, Gerold KB, Hang J, Smith TH. Recovery room delirium 
predicts postoperative delirium after hip-fracture repair. Anesth Analg. 2005 Oct; 101(4): 1215-20, table of contents. 
27. O'Regan NA, Fitzgerald J, Timmons S, O'Connell H, Meagher D. Delirium: A key challenge for perioperative 
care. Int J Surg. 2013; 11(2): 136-144. 
28. Bruce AJ, Ritchie CW, Blizard R, Lai R, Raven P. The incidence of delirium associated with orthopedic surgery: 
A meta-analytic review. Int Psychogeriatr. 2007 Apr; 19(2): 197-214. 
29. Young J, Inouye SK. Delirium in older people. BMJ. 2007 Apr 21; 334(7598): 842-846. PMCID: PMC1853193. 
30. Sanders RD, Pandharipande PP, Davidson AJ, Ma D, Maze M. Anticipating and managing postoperative 
delirium and cognitive decline in adults. BMJ. 2011 Jul 20; 343: d4331. 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
17JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 17 of 20 
 
31. Rudolph JL, Jones RN, Levkoff SE, Rockett C, Inouye SK, Sellke FW, Khuri SF, Lipsitz LA, Ramlawi B, 
Levitsky S, Marcantonio ER. Derivation and validation of a preoperative prediction rule for delirium after cardiac 
surgery. Circulation. 2009 Jan 20; 119(2): 229-236. 
32. Rudolph JL, Jones RN, Rasmussen LS, Silverstein JH, Inouye SK, Marcantonio ER. Independent vascular and 
cognitive risk factors for postoperative delirium. Am J Med. 2007 Sep; 120(9): 807-813. 
33. Rudolph JL, Inouye SK, Jones RN, Yang FM, Fong TG, Levkoff SE, Marcantonio ER. Delirium: An 
independent predictor of functional decline after cardiac surgery. J Am Geriatr Soc. 2010 Apr; 58(4): 643-649. 
PMCID: PMC2856754. 
34. Trompeo AC, Vidi Y, Locane MD, Braghiroli A, Mascia L, Bosma K, Ranieri VM. Sleep disturbances in the 
critically ill patients: Role of delirium and sedative agents. Minerva Anestesiol. 2011 Jun; 77(6): 604-612. 
35. Maldonado JR. Neuropathogenesis of delirium: Review of current etiologic theories and common pathways. Am 
J Geriatr Psychiatry. 2013 Dec; 21(12): 1190-1222. 
36. de Rooij SE, van Munster BC, de Jonghe A. Melatonin prophylaxis in delirium: Panacea or paradigm shift? 
JAMA Psychiatry. 2014 Feb 19. 
37. Brzezinski A. Melatonin in humans. N Engl J Med. 1997 Jan 16; 336(3): 186-195. 
38. Borjigin J, Li X, Snyder SH. The pineal gland and melatonin: Molecular and pharmacologic regulation. Annu Rev 
Pharmacol Toxicol. 1999; 39: 53-65. 
39. Cardinali DP, Srinivasan V, Brzezinski A, Brown GM. Melatonin and its analogs in insomnia and depression. J 
Pineal Res. 2012 May; 52(4): 365-375. 
40. Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, Hardeland R, Cardinali DP. 
Melatonin antioxidative defense: Therapeutical implications for aging and neurodegenerative processes. Neurotox 
Res. 2013 Apr; 23(3): 267-300. 
41. Lee EJ, Lee MY, Chen HY, Hsu YS, Wu TS, Chen ST, Chang GL. Melatonin attenuates gray and white matter 
damage in a mouse model of transient focal cerebral ischemia. J Pineal Res. 2005 Jan; 38(1): 42-52. 
42. Lee EJ, Wu TS, Lee MY, Chen TY, Tsai YY, Chuang JI, Chang GL. Delayed treatment with melatonin enhances 
electrophysiological recovery following transient focal cerebral ischemia in rats. J Pineal Res. 2004 Jan; 36(1): 33-
42. 
43. Lee MY, Kuan YH, Chen HY, Chen TY, Chen ST, Huang CC, Yang IP, Hsu YS, Wu TS, Lee EJ. Intravenous 
administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal 
cerebral ischemia in rats. J Pineal Res. 2007 Apr; 42(3): 297-309. 
44. Rezzani R, Rodella LF, Bonomini F, Tengattini S, Bianchi R, Reiter RJ. Beneficial effects of melatonin in 
protecting against cyclosporine A-induced cardiotoxicity are receptor mediated. J Pineal Res. 2006 Oct; 41(3): 288-
295. 
45. Mathes AM, Kubulus D, Weiler J, Bentley A, Waibel L, Wolf B, Bauer I, Rensing H. Melatonin receptors 
mediate improvements of liver function but not of hepatic perfusion and integrity after hemorrhagic shock in rats. 
Crit Care Med. 2008 Jan; 36(1): 24-29. 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
18JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 18 of 20 
 
46. Mathes AM, Kubulus D, Pradarutti S, Bentley A, Weiler J, Wolf B, Ziegeler S, Bauer I, Rensing H. Melatonin 
pretreatment improves liver function and hepatic perfusion after hemorrhagic shock. Shock. 2008 Jan; 29(1): 112-
118. 
47. Rathnasamy G, Ling EA, Kaur C. Therapeutic implications of melatonin in cerebral edema. Histol Histopathol. 
2014 May 29. 
48. Chen HY, Chen TY, Lee MY, Chen ST, Hsu YS, Kuo YL, Chang GL, Wu TS, Lee EJ. Melatonin decreases 
neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier 
permeability after transient focal cerebral ischemia in mice. J Pineal Res. 2006 Sep; 41(2): 175-182. 
49. Chen TY, Lee MY, Chen HY, Kuo YL, Lin SC, Wu TS, Lee EJ. Melatonin attenuates the postischemic increase 
in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator 
therapy following ischemic stroke in mice. J Pineal Res. 2006 Apr; 40(3): 242-250. 
50. Trzepacz PT. Update on the neuropathogenesis of delirium. Dement Geriatr Cogn Disord. 1999 Sep-Oct; 10(5): 
330-334. 
51. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of 
delirium: A focus on the role of aberrant stress responses. J Psychosom Res. 2008 Sep; 65(3): 229-238. 
52. Cunningham C, Skelly DT. Non-steroidal anti-inflammatory drugs and cognitive function: Are prostaglandins at 
the heart of cognitive impairment in dementia and delirium? J Neuroimmune Pharmacol. 2012 Mar; 7(1): 60-73. 
PMCID: PMC3280386. 
53. Maldonado JR. Pathoetiological model of delirium: A comprehensive understanding of the neurobiology of 
delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008 Oct; 24(4): 789-856, ix. 
54. Cronin AJ, Keifer JC, Davies MF, King TS, Bixler EO. Melatonin secretion after surgery. Lancet. 2000 Oct 7; 
356(9237): 1244-1245. 
55. Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M, Miura M, Menjo M, Ikeda K. Postoperative delirium 
and melatonin levels in elderly patients. Am J Surg. 2001 Nov; 182(5): 449-454. 
56. Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma melatonin 
concentration in postoperative critically ill patients: Its association with delirium. J Crit Care. 2013 Jun; 28(3): 236-
242. 
57. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium 
after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010 Sep; 4(3): 169-173. PMCID: 
PMC2980663. 
58. de Jonghe A, van Munster BC, Goslings JC, Kloen P, van Rees C, Wolvius R, van Velde R, Levi M, de Haan RJ, 
de Rooij SE, de Rooij SE, on behalf of the Amsterdam Delirium Study Group. Effect of melatonin on incidence of 
delirium among patients with hip fracture: A multicentre, double-blind randomized controlled trial. CMAJ. 2014 Sep 
2. 
59. Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases 
delirium in elderly patients: A randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011 Jul; 26(7): 687-
694. 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
19JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 19 of 20 
 
60. DailyMed current medication information website [homepage on the Internet]. . Available from: 
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7a51d289-2013-4d37-adf2-91ea49df7932. 
61. American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental 
disorders: DSM-IV : International version with ICD-10 codes. 4th , international version ed. Washington, DC: 
American Psychiatric Association; 1995. 
62. Trzepacz PT, Mittal D, Torres R, Kanary K, Norton J, Jimerson N. Validation of the delirium rating scale-
revised-98: Comparison with the delirium rating scale and the cognitive test for delirium. J Neuropsychiatry Clin 
Neurosci. 2001 Spring; 13(2): 229-242. 
63. van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, Spronk PE, van Gool WA, van der 
Mast RC, Kesecioglu J, Slooter AJ. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of 
delirium and mortality in critically ill patients: A multicentre, double-blind, placebo-controlled randomised trial. 
Lancet. 2010 Nov 27; 376(9755): 1829-1837. 
64. Girard TD, Pandharipande PP, Carson SS, Schmidt GA, Wright PE, Canonico AE, Pun BT, Thompson JL, 
Shintani AK, Meltzer HY, Bernard GR, Dittus RS, Ely EW, for the MIND TI. Feasibility, efficacy, and safety of 
antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial. Crit Care Med. 
2010; 38: 428-437. 
65. Page VJ, Ely EW, Gates S, Zhao XB, Alce T, Shintani A, Jackson J, Perkins GD, McAuley DF. Effect of 
intravenous haloperidol on the duration of delirium and coma in critically ill patients (hope-ICU): A randomised, 
double-blind, placebo-controlled trial. Lancet Respir Med. 2013 Sep; 1(7): 515-523. 
66. Friedman JI, Soleimani L, McGonigle DP, Egol C, Silverstein JH. Pharmacological treatments of non-substance-
withdrawal delirium: A systematic review of prospective trials. Am J Psychiatry. 2014 Feb 1; 171(2): 151-159. 
67. Kales HC, Kim HM, Zivin K, Valenstein M, Seyfried LS, Chiang C, Cunningham F, Schneider LS, Blow FC. 
Risk of mortality among individual antipsychotics in patients with dementia. Am J Psychiatry. 2012 Jan; 169(1): 71-
79. 
68. Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: Meta-
analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006 Mar; 14(3): 191-210. 
69. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: 
Meta-analysis of randomized placebo-controlled trials. JAMA. 2005 Oct 19; 294(15): 1934-1943. 
70. Zhdanova IV. Melatonin as a hypnotic: Pro. Sleep Med Rev. 2005 Feb; 9(1): 51-65. 
71. Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf. 2009; 32(9): 735-748. 
72. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005 Aug 4; 353(5): 487-497. 
73. Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for subsyndromal delirium after on-pump 
cardiac surgery in the elderly: A randomized trial. Anesthesiology. 2012; 116: 987-997. 
74. Silverstein JH, Deiner SG. Perioperative delirium and its relationship to dementia. Prog Neuropsychopharmacol 
Biol Psychiatry. 2012; 43C: 108-115. 
75. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of 
patients for the clinician. J Psychiatr Res. 1975 Nov; 12(3): 189-198. 


Date: 12/18/17 
Principal Investigator: Karin J Neufeld 
Application Number: IRB00097232  
 
 
 
20JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 20 of 20 
 
76. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horowitz RI. Clarifying confusion: The confusion 
assessment method. A new method for detection of delirium. Ann Intern Med. 1990; 113(12): 941-948. 
77. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, 
Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der 
Poll T, Vincent JL, Angus DC. The third international consensus definitions for sepsis and septic shock (sepsis-3). 
JAMA. 2016 Feb 23; 315(8): 801-810. 
78. Roth T, Seiden D, Wang-Weigand S, Zhang J. A 2-night, 3-period, crossover study of ramelteon's efficacy and 
safety in older adults with chronic insomnia. Curr Med Res Opin. 2007 May; 23(5): 1005-1014. 
79. Wurtman R. Ramelteon: A novel treatment for the treatment of insomnia. Expert Rev Neurother. 2006 Jul; 6(7): 
957-964. 
80. Wechsler D, editor. Wechsler adult intelligence scale. Third ed. San Antonio: The Psychological Corporation 
Harcourt Brace & Company; 1997. 
81. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: The confusion 
assessment method. A new method for detection of delirium. Ann Intern Med. 1990 Dec 15; 113(12): 941-948. 
82. Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, 
Hart RP, Dittus R. Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment 
method for the intensive care unit (CAM-ICU). JAMA. 2001 Dec 5; 286(21): 2703-2710. 
83. Jorm AF. The informant questionnaire on cognitive decline in the elderly (IQCODE): A review. Int 
Psychogeriatr. 2004 Sep; 16(3): 275-293. 
84. Morris JC. The clinical dementia rating (CDR): Current version and scoring rules. Neurology. 1993 Nov; 43(11): 
2412-2414. 
85. KATZ S, FORD AB, MOSKOWITZ RW, JACKSON BA, JAFFE MW. Studies of illness in the aged. the index 
of adl: A standardized measure of biological and psychosocial function. JAMA. 1963 Sep 21; 185: 914-919. 
86. Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the index of ADL. Gerontologist. 1970 
Spring; 10(1): 20-30. 
87. Lawton MP, Brody EM. Assessment of older people: Self-maintaining and instrumental activities of daily living. 
Gerontologist. 1969 Autumn; 9(3): 179-186. 
88. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in 
longitudinal studies: Development and validation. J Chronic Dis. 1987; 40(5): 373-383. 
89. ASA physical status classification system [homepage on the Internet]. . Available from: 
http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status-Classification-System. 
90. Buysse DJ, Reynolds CF,3rd, Monk TH, Berman SR, Kupfer DJ. The pittsburgh sleep quality index: A new 
instrument for psychiatric practice and research. Psychiatry Res. 1989 May; 28(2): 193-213. 
91. Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline 
comparisons in clinical trial reporting: Current practice and problems. Stat Med. 2002 Oct 15; 21(19): 2917-2930. 
92. Diggle PJ, Liang KY, and Zeger SL. Analysis of longitudinal data. Oxford: Clarendon Press; 1994 

ICF_001.pdf: 
 
 
A Randomized Double Blind Placebo 
Controlled Trial of Ramelteon in the 
Prevention of Postoperative Delirium in 
Older Patients Undergoing Orthopedic 
Surgery: The RECOVER Study 
R21 AG050850-01A1 
NCT02324153 
 
Consent Form 
 
Date of Last IRB Approval: 7/12/19 
Johns Hopkins University School of 
Medicine 
Karin J Neufeld MD MPH 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 2 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title:  
“A Randomized Double Blind Placebo Controlled Trial of 
Ramelteon in the Prevention of Post-operative Delirium in Older 
Patients Undergoing Orthopedic Surgery" (AKA: The RECOVER 
Study) 
Application No.:  
IRB00097232 
 
Sponsor:  
NIH – National Institute on Aging 
 
Principal Investigator:  Karin J. Neufeld 
Department of Psychiatry and Behavioral Sciences 
Johns Hopkins Bayview Medical Center 
A4 Center Suite 457; 4940 Eastern Ave. Baltimore, MD 21224 
Phone 401-550-0197 (o) 443-691-8305 (c)  
email: kneufel2@jhmi.edu 
 
1. 
What you should know about this study: 
 You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand. 
 You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty 
or loss of benefits if you decide to quit the study.   
 During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate. 
 If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins.   
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research 
team to send this information to any of your doctors. 
 When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The 
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital.  
 Biospecimens will be collected in this study.  Biospecimens may include any of the following: 
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person. 
 A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
 If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number. 
 During this study, you will not have access to certain medical information and test results collected 
for study purposes.  If an emergency occurs while you are in the study, medical information needed 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 3 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
for your treatment can be made available to your study physician and other physicians who treat you.  
When the study is completed, all the information in your medical record will be available to you. 
 The person being asked to be in this research study may not be able to give consent to be in this 
study.  You are therefore being asked to give permission for this person to be in the study as his/her 
decision maker.  
 
2. 
Why is this research being done? 
This research is being done to test the use of a study drug called Ramelteon to prevent delirium after 
surgery.   
 
Ramelteon (also known as Rozerem) is approved by the Food and Drug Administration (FDA) for the 
treatment of insomnia or difficulties falling asleep.  It is not approved for preventing delirium and its use 
in the study is considered investigational.   
 
Delirium is a sudden change in ability to think and remember that isn’t like the person when they are at 
their best. Sleep problems are also common during delirium.  Delirium is caused by an underlying 
physical disturbance and generally lasts several days.   It can happen sometimes after having surgery and 
is called “post-operative delirium”. It can result in significant problems, such as slower recovery from 
surgery, need for longer hospital and rehabilitation stays, increased costs to the healthcare system and it 
can be frightening for both patients and their families.  
 
There is no cure for delirium or any medication proven to prevent it.  This study will compare the 
number of people who develop delirium while receiving the study drug, ramelteon, given before and two 
nights after their surgery to those who do not receive this drug and receive a placebo instead. We will 
also study whether certain chemicals in the blood and brain can predict delirium after surgery and 
whether Ramelteon can change these chemicals. 
 
People, 65 years of age or older, undergoing orthopedic surgery may join.  
 
How many people will be in this study? 
We will ask at least 80 people to join the study.  It will take place at one hospital - the Johns Hopkins 
Bayview Medical Center.   
 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you to do the following things: 
 
Before Surgery 
If you are not admitted to the hospital before your surgery we will make an appointment to meet with 
the research team at the Johns Hopkins Bayview Medical Center. During that visit you will be asked 
some more questions about your health and thinking.   We will ask a family member or friend some 
questions about your health as well. All of these questions will take about 1 hour.  
 
We will also draw 1 teaspoon of blood for research purposes at the same time.  You do not have to have 
blood drawn for research to be in this study.  
 
At the end of that visit our pharmacist at the hospital will prepare the study drug for you to take home.  
You will be given one capsule to take the night before surgery.  It will contain either ramelteon or 
placebo (an inactive material that does not contain any active study drug).  The research pharmacist at 
Bayview will be the only person who knows which type of study drug you received. A computer will 
decide which type of medication you get, much like a “flip of a coin”. Your doctors, nurses, and study 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 4 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
staff will not know what kind of study drug you received.  However the study doctor can quickly get the 
information from the pharmacist if needed in a medical emergency.  
 
If you are unable or do not want to come to the hospital for the baseline visit, the study team might be 
able to visit you in the community before your surgery if you prefer.  If you live too far away for the 
team to visit in person, we can send you this consent sign electronically after the medical team discusses 
it with you by telephone to answer your questions.  
 
The study staff will call you the night before surgery to remind you to take the capsule at bedtime.   
 
Both kinds of capsules (ramelteon and placebo) will also contain vitamin B2, riboflavin. We will test 
your urine to see if it has riboflavin in it on the day of surgery. This helps us be sure that you took the 
pill before surgery.  
  
After Surgery 
The study the research staff will come and see you after you awake from anesthesia after the surgery and 
are ready to be moved to the hospital ward. Research assistants will ask you some questions about your 
thinking.  This will take about 5 to 10 minutes.   
 
You will receive the same type of study drug (either ramelteon or placebo) for two nights while you are 
in the hospital – on the night of surgery and the first night after. The nurse caring for you on the surgical 
ward will give it to you at bedtime. On the first and second days after surgery the research staff will 
review your hospital chart, and will ask you some questions about your thinking and your physical 
symptoms. If you are discharged prior to your second day after surgery, you be given your study drug 
(either ramelteon or placebo) to take at your place of discharge.  In addition, the research staff will call 
you to complete questionnaires.  The study ends on the second day following your surgery.  
 
We will draw 1 teaspoon of blood for research purposes on both the first and second days after surgery. 
If you are discharged from the hospital early (prior to day two after surgery), the blood draw for that day 
will not be completed. 
 
Request to contact you after the study is completed?  
We do not plan to contact you after the study ends at this time.  Would you allow us to contact you 
following the study if we have more questions at that time?   
 
YES     ________________________   
 
 
 
Signature of Participant 
 
 
 
 
 
 
NO      __________________  
 
 
 
Signature of Participant 
 
 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 5 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
Request to collect and store biospecimens for future research   
As part of this research study, we would like to ask you to let us store your biospecimens and health 
information for future research.  This research could include other diseases. 
 
The study doctor can provide you with additional information if you have questions. Also, further 
information about our use of your biospecimens can be found in this consent document under the 
heading “What happens to Data and Biospecimens that are collected in the study?”. 
 
Will you allow us to store the biospecimens we collect for this study for use in future research? 
 
YES     ________________________   
 
 
 
Signature of Participant 
 
 
 
 
 
 
NO      __________________  
 
 
 
Signature of Participant 
 
 
 
 
 
 
How long will you be in the study? 
You will be in this study for 2 days after your surgery. 
 
4. 
What are the risks or discomforts of the study? 
Risks Associated with the Study Drug: Ramelteon 8 mg 
The main risk of taking ramelteon is that instead of decreasing delirium, it may make no difference or it 
may make delirium worse.  
 
Other risks associated with ramelteon reported in product labeling by the company include:   
1. Less rare and less serious side effects such as somnolence (sleepiness), fatigue, dizziness, nausea 
and worsened insomnia;  
2. Rarely new cognitive or behavioral abnormalities that may be the result of an unrecognized 
underlying psychiatric or physical disorder, such as worsening of depression (including suicidal 
ideation and completed suicides), hallucinations, bizarre behavior, agitation and mania;  
3. Very rarely amnesia (or loss of memory), anxiety and other complex behaviors such as "sleep-
driving" (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex 
behaviors (e.g., preparing and eating food, making phone calls, or having sex) with amnesia for 
the event; 
4. Extremely rare but potentially life threatening side effects include angioedema (swelling similar 
to hives that may develop under the skin) and anaphylactic reactions (severe allergic reactions);  
5. Decreased testosterone levels and increased prolactin levels have been reported with long-term 
use;  
6. Ramelteon should not be given to people taking the following medications: fluvoxamine 
(Luvox), melatonin, rifampin (Rifadin, Rimactane), ketoconazole (Nizoral), fluconazole 
(Diflucan)  
 
Risks Associated with the Tracer Substance – Riboflavin (Vitamin B2) 100 mg 
Riboflavin can be associated with an allergic reaction.  Anyone with a riboflavin allergy should not take 
part in this study.  
 
Risks Associated with the Study Procedures 
Having blood drawn may cause some pain and a bruise may form where the needle enters the vein. 
Drawing blood may cause some people to faint.  There is a rare risk of infection from inserting the 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 6 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
needle, however the blood drawn after surgery will be drawn at the same time as your other routine 
blood draws during hospitalization so that there is no extra needle stick.   
 
There is the risk that information about you may become known to people outside this study.  We will 
do everything that we can to ensure that your information and confidentiality is protected.    
 
You may get tired or bored when we are asking you questions or you are completing questionnaires. 
You do not have to answer any question you do not want to answer. 
 
There may be side effects and discomforts that are not yet known.  
 
5. 
Are there benefits to being in the study? 
There may or may not be a direct benefit to you from being in the study. If ramelteon can prevent post-
operative delirium receiving the study drug in this study might result in some benefit but this cannot be 
guaranteed. No benefit is expected if you are randomly assigned to receive placebo. If you take part in 
this study, you may help others in the future. 
 
6. 
What are your options if you do not want to be in the study? 
You do not have to join this study.  If you do not join, your care at Johns Hopkins will not be affected. 
 
7. 
Will it cost you anything to be in this study?   
You will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet).  
 
This Sheet will give you the following information: 
 
 The procedures, tests, drugs or devices that are part of this research and that will be paid for by 
the study (no cost to you).   
 
 The procedures, tests, drugs or devices that will be billed to you and/or your health insurer.  If 
you have health insurance, you will be responsible for any co-pays or deductibles not covered by 
your insurance.  
 
8. 
Will you be paid if you join this study? 
We will pay for $50 if you come to the Johns Hopkins Bayview Medical Center in order to complete 
your baseline visit prior to your surgery.  
 
You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your total 
payments from Johns Hopkins exceed $600 per year, Johns Hopkins will report these payments to the 
Internal Revenue Service and you will receive a 1099-MISC form from us.  
 
9. 
Can you leave the study early? 
 You can agree to be in the study now and change your mind later. 
 If you wish to stop, please tell us right away. 
 Leaving this study early will not stop you from getting regular medical care.  
 
If you leave the study early, Johns Hopkins may use or give out your health information that it has 
already collected if the information is needed for this study or any follow-up activities.  


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 7 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
 
10. 
Why might we take you out of the study early?  
You may be taken out of the study if: 
 Staying in the study would be harmful. 
 You need treatment not allowed in the study. 
 If your surgery is canceled and rescheduled to a date less than 7 days after taking the first dose of 
medication. 
 The study is cancelled. 
 There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities. 
 
11. 
How will your privacy be protected?  
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule. 
 
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and information from your medical records (which may include 
information about HIV status, drug, alcohol or STD treatment, genetic test results, or mental health 
treatment). 
 
The research team will know your identity and that you are in the research study.  Other people at Johns 
Hopkins, particularly your doctors, may also see or give out your information. We make this information 
available to your doctors for your safety.    
 
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study.  
 
If you are in a cancer study that receives federal funding, the National Cancer Institute (NCI) now 
requires that we report identifiable information (such as, zip code) about your participation.  You may 
contact the NCI if you have questions about how this information is used.  
 
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be re-
disclosed. 
 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form.  


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 8 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
 
12. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins and the federal government do not have a program to pay you if you are hurt or have 
other bad results from being in the study.  However, medical care at Johns Hopkins is open to you as it 
is to all sick or injured people.   
 
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you. 
 
By signing this form you will not give up any rights you have to seek compensation for injury.  
 
13. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
The Johns Hopkins Medicine IRB is made up of: 
 Doctors 
 Nurses 
 Ethicists 
 Non-scientists 
 and people from the local community.  
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.   
 
b. What do you do if you have questions about the study?    
Call the principal investigator or study doctor, Dr. Karin Neufeld at 410-550-0197 during business 
hours. If you wish, you may contact the principal investigator by letter or by fax.  The address and 
fax number are on page one of this consent form. If you cannot reach the principal investigator or 
wish to talk to someone else, call the IRB office at 410-955-3008.   
 
c. What should you do if you are injured or ill as a result of being in this study?  
If you think you are injured or ill because of this study, call Dr. Karin Neufeld at 443-691-8305.  
 
If you have an urgent medical problem related to your taking part in this study, call Dr. Karin 
Neufeld at 410-550-0197 during regular office hours or 443-691-8305 after hours and on weekends.  
 
d. What happens to Data and Biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to understand and cure diseases. The biospecimens 
and/or data you provide are important to this effort. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 9 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.  
 
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.  
  
14. 
What does your signature on this consent form mean?  
Your signature on this form means that: You understand the information given to you in this form, you accept the 
provisions in the form and you agree to join the study. You will not give up any legal rights by signing this 
consent form.  
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                                            
(Print Name)                                                 
Date/Time  
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                   
(Print Name)                                             
Date/Time 
 
 
________________________________________________________________________________________________________________________ 
Signature of Legally Authorized Representative (LAR)                         
(Print Name)                                            
Date/Time    
For ADULTS NOT CAPABLE of GIVING CONSENT (Persons from the following categories in order of 
priority may be a Legally Authorized Representative: Health Care Agent; Legal Guardian;  
Spouse; Adult child; Parent; Adult sibling; Friend or other relative)  
 
 
 
________________________________________________________________________________________________________________________ 
Relationship of LAR to Participant (indicate why the LAR is authorized                                                         
 
Date/Time 
to act as a surrogate health care decision-maker under  state or applicable local law) 
 
 
___________________________________________________________________________________________________________ 
Signature of Participant, LAR or Parent/Guardian                                 
(Print Name)                                                         Date/Time 
 
 
I have received the separate Insurance and Research Participant Financial Responsibility Information Sheet.   
 
 
___________________________________________________________________________________________________________ 
Signature of Participant, LAR or Parent/Guardian                               
 (Print Name)                                                         Date/Time 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY 
MUST BE GIVEN TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-
7382; IF YOU ARE NOT USING EPIC A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO 
MEDICAL RECORD EXISTS OR WILL BE CREATED).  
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT 
OF RESEARCH PARTICIPANTS. 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: October 8, 2017  
Principal Investigator: Karin J. Neufeld MD MPH 
Application No.: IRB00097232 
 
Page 10 of 10 
Combined Informed Consent/Authorization June 2015 Version 15 
DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT 
 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study. 
 
 
________________________________________________________________________________________________________________________ 
Signature of Physician/Mid-Level Provider                     (Print Name)                                                                     
 
Date/Time   
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                    (Print Name)                                                                    
 
Date/Time     
 
 
________________________________________________________________________________________________________________________ 
Signature of Legally Authorized Representative (LAR)                       (Print Name)                                                    
 
Date/Time    
For ADULTS NOT CAPABLE of GIVING CONSENT (Persons from the following categories in order of 
priority may be a Legally Authorized Representative: Health Care Agent; Legal Guardian;  
Spouse; Adult child; Parent; Adult sibling; Friend or other relative)  
 
 
________________________________________________________________________________________________________________________ 
Relationship of LAR to Participant (indicate why the LAR is authorized                                                         
 
Date/Time 
to act as a surrogate health care decision-maker under state or applicable local law) 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY 
MUST BE GIVEN TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-
7382; IF YOU ARE NOT USING EPIC A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO 
MEDICAL RECORD EXISTS OR WILL BE CREATED).  
 
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT 
OF RESEARCH PARTICIPANTS.