Melatonin Use After Primary Total Joint Arthroplasty: A Randomized, Double Blind Placebo-Controlled Trial
Phase: PHASE1
Conditions: Osteo Arthritis Knee
Sponsor: NYU Langone Health

Official Title: 
Melatonin Use After Primary Total Joint Arthroplasty: A Randomized, 
Double Blind Placebo-Controlled Trial  
NCT Number:
NCT04795336
Study Number:
20-02030 
Document Type:
Study Protocol and Statistical Analysis Plan
Date of the 
Document: 
 
December 16, 2021 
  

Study number: i20-02030
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MELATONIN USE AFTER PRIMARY TOTAL JOINT ARTHROPLASTY: 
A RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED TRIAL 
A Phase 1, randomized control trial, single-center study of the effect of melatonin supplementation on 
early postoperative outcomes and sleep quality 
Principal Investigator:
Joshua Rozell, MD
Department of Orthopedic Surgery
Joshua.Rozell@nyulangone.org 
212-598-6245 
NYULMC Study Number: 
Funding Sponsor:  
NYU Langone Department of Orthopedic Surgery 
IND/IDE Number: 
n/a
Regulatory Sponsor: 
n/a 
Study Product:
Melatonin
Study Product Provider:  
n/a 
ClinicalTrials.gov 
Number
 
n/a 
Statement of Compliance 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 

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Protocol Summary
Title 
MELATONIN USE AFTER PRIMARY TOTAL JOINT ARTHROPLASTY: A 
RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED TRIAL 
Brief Summary 
The purpose of this study is to determine the effect
of melatonin 
supplementation on patient sleep quality, length of stay, and opioid 
consumption following primary, unilateral, elective total hip or knee 
arthroplasty. 
 
Phase 
N/A 
Objectives 
The primary objective is improved sleep quality postoperatively  
Methodology 
Single Center, randomized, double-blind, placebo-controlled clinical trial 
Endpoint 
The primary endpoint will be enrollment and completion of the study of 256 
patients as pre-determined by statistical analysis.
Study Duration 
Approximately 12 months (post IRB approvals) 
Participant Duration 
We estimate each patient will need to participate for roughly 60 days 
Duration of IP 
administration 
Patients will take the melatonin or placebo for 14 days  
Population 
Sample size will be 252 patients, both male and female patients will be 
included, all adult patients undergoing primary elective TKA or THA will be 
included. No vulnerable populations will be enrolled 
Study Sites 
Langone Orthopedic Hospital, New York, NY
NYU Brooklyn Hospital, Brooklyn, NY
Number of participants 
256 participants  
Description of Study 
Agent/Procedure 
Melatonin is an over-the-counter sleep aid 
Reference Therapy 
None 
Key Procedures
Pre- and postoperative sleep survey, survey on quality of sleep, patient 
reported outcome questionnaires, narcotic consumption and pain daily for 14 
days postoperatively  
Statistical Analysis 
Descriptive statistics will be used to report baseline characteristics and
primary study objectives 
 

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1
Introduction, Background Information and Scientific Rationale
1.1
Background Information and Relevant Literature
Utilization of total hip and knee arthroplasty (THA and TKA, respectively) has increased over the last decade 
and is expected to continue to rise as the population of the United States ages. By 2030, over 2 million total 
joint arthroplasty (TJA) procedures are anticipated to be performed annually1. With increasing numbers and 
to maintain excellent patient outcomes after total joint arthroplasty, it has become important to optimize 
every aspect of patient recovery. Sleep disturbance is a routinely encountered problem during the 
perioperative period in adults undergoing elective surgery2. Sleep in postoperative patients is negatively 
influenced by exposure to anesthesia3, 4 and the presence of postoperative pain5. Reciprocally, poor sleep 
also portends poor coping and exacerbation of post-operative pain6, 7. Nighttime awakenings may be 
frequent, and require the use of additional pain medication to go back to sleep. 
1.2
Name and Description of the Investigational Agent 
1.2.1
Preclinical Data
Melatonin or 5 methoxy-N-acetyltryptamine was discovered and isolated from bovine pineal gland in 19578. 
A naturally occurring hormone, melatonin is synthesized by pinealocytes from tryptophan and once 
synthesized released into the systemic circulation to reach several central and peripheral target tissues9. 
Melatonin works through activation of ML1 and ML2 receptors in target cells through a G-protein coupled 
receptor – adenyl cyclase pathways8, 10. The molecule is important in regulation of human circadian rhythms 
such as the sleep-wake rhythm, neuroendocrine rhythms or body temperature cycles through its action on 
various target cells throughout the body11. Consumption of melatonin, either orally or intravenously, induces 
fatigue, sleepiness and a diminution of sleep latency in humans12. Given its physiologic effects, melatonin 
is an agent of great interest in perioperative patients experiencing sleep disturbance.  
 
1.2.2 Clinical Data to Date 
Decreased levels of melatonin production have been observed in postoperative patients undergoing minor 
orthopedic procedures whether under general or regional anesthesia13. Perioperative melatonin has been 
studied in other fields of surgery. Caumo et al have demonstrated preoperative administration of melatonin 
has been associated anxiolytic and analgesic effects in addition to increased potency of sleep/wake 
circadian rhythms in patients undergoing gynecologic procedures14, 15. Borazan et al demonstrated 
improved subjective sleep quality after prostate surgery after perioperative administration of melatonin16. A 
systematic review of randomized trials with melatonin has demonstrated efficacy in reducing perioperative 
anxiety and some positive effects on perioperative pain17. 
1.3 Rationale 
Sleep disruption following elective, primary total joint arthroplasty is very common. The cause is likely 
multifactorial, resulting from anxiety, anesthesia, the patient’s recovery environment, and pain. Overall 
tiredness can lead to decreased energy, restlessness, less ambulation, and slow progress with physical 
therapy and recovery. Melatonin is an inexpensive, over the counter dietary supplement with an established 
safety profile that has been used to help create a more restful sleep cycle. There is no consensus as to the 
utility, dose, duration, or timing of melatonin administration in the period before and after elective hip and 
knee arthroplasty to improve sleep quality. This study design is supported by sleep disturbance usually 
occurs within the first 2 weeks of surgery due to a disrupted sleep wake cycle and pain. 5mg is a safe and 
effective starting dose for any sleep disturbance.20 Further, inconsistent methods of assessing patients’ 
sleep and pain postoperatively has made the study of sleep quality difficult. 

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1.4
Potential Risks & Benefits
1.4.1 Known Potential Risks 
Short term use of melatonin is safe, even in extreme doses with only mild adverse effects which can 
include dizziness, headache, nausea and sleepiness18. Randomized clinical studies have indicated that 
even long-term exogenous melatonin only mild adverse effects such as dizziness and headaches 
comparable to placebo17. 
1.4.2 Known Potential Benefits 
In addition to its importance in in regulation of human circadian rhythms such as the sleep-wake rhythm, 
neuroendocrine rhythms or body temperature cycles; perioperative melatonin is also known to reduce the 
incidence of delirium in older patients19.  
2 Objectives and Purpose 
2.1 Primary Objective 
The primary objective is the Epworth Sleep Score used to evaluate the impact of melatonin use on the 
quality of sleep, including total hours of sleep and nighttime awakenings in patients undergoing elective 
primary total hip and knee arthroplasty. 
Secondary Objectives are to monitor and investigate hospital length of stay, and narcotic consumption 
patterns, scores in patients who take melatonin as a sleep aid for 14 days after surgery. 
3 Study Design and Endpoints 
3.1 Description of Study Design
This will be a single-center randomized double blind placebo control clinical trial. In the cohort of patients 
undergoing primary elective total hip and the cohort of patients undergoing primary elective knee 
arthroplasty, participants are recruited from those who are willing to consent and participate in the study, 
and will be randomly 1:1 divided into intervention group and placebo group.  
Knee cohort: 
 
Intervention group will receive a 5mg Melatonin prescription for 14 days 
 
Control group will receive a placebo pill for 14 days 
Hip cohort: 
 
Intervention group will receive a 5mg Melatonin prescription for 14 days 
 
Control group will receive a placebo pill for 14 days 
 
3.2 Study Endpoints 
3.2.1 Primary Study Endpoints 
The primary endpoint will be the Epworth Sleep Score for patients indicating the impact of melatonin on 
quality of sleep, including total hours of sleep and nighttime awakening. The ESS will be evaluated post-
operatively from days 1-14. 
4 Study Enrollment and Withdrawal 
4.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 

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1. Patient are current candidates for elective primary total hip or total knee arthroplasty 
2. 
18 years of age but  95 
3. Patients have been medically cleared and scheduled for surgery 
4.2
Exclusion Criteria
An individual who meets any of the following criteria will be excluded from participation in this study:
 
Non-elective conversion arthroplasty 
 
Consistent melatonin use within 1 month of surgery 
 
Bilateral total joint arthroplasty 
 
Contraindications to use of melatonin (diabetes, calcium channel blocker use, depression) 
 
Conditions and medications likely to confound results due to impact on subjective and/or objective 
sleep quality (insomnia, drug/alcohol abuse, and use of benzodiazepines, and prescription sleep 
aids) 
 
Conditions likely to impair capacity to adhere to protocol (mental impairment, psychiatric disorders 
other than anxiety/depression) 
4.3 Vulnerable Subjects 
No Vulnerable subjects will be enrolled in this study 
4.4 Duration of Study Participation
Participants will be enrolled for approximately 2months after surgery. 
4.5 Total Number of Participants and Sites  
252 patients will be recruited at NYU Langone Orthopedic Hospital and NYU Brooklyn Hospital. 
4.6 Participant Withdrawal or Termination 
4.6.1 Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may terminate participation in the study if: 
 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
4.6.2 Handling of Participant Withdrawals or Termination 
Any patient that wishes to withdraw or in whom a clinical adverse effect is noticed, will be allowed to do 
so without recourse. They will still be given appropriate standard of care follow-up as would be given any 
pre- or post-operative TJA patient. If a patient is presumed lost to follow-up they will be contacted via 
phone-calls and certified letters, which will be tracked. There is no safety risk predicted from abrupt 
termination. Any patients who withdraw or discontinue early will be replaced via recruitment of new 
patients. As LOH is a high-volume arthroplasty center performing thousands of primary TJA procedures 
there is not expected to be an issue in recruiting new subjects as approximately 10-50% of patients are 
projected to be affected by malnutrition (previously cited data). 
 
4.7 Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 

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by the suspending or terminating party to the IRB. If the study is prematurely terminated or suspended, 
the PI will promptly inform the IRB and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the IRB.  
5 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention  
5.1 Study Agent(s) and Control Description
Melatonin, as previously described, is a widely available over the counter sleep aid.  
5.1.1 Acquisition 
Melatonin will be ordered in bulk from a generic retail option that can be found. Once ordered it will be 
shipped via standard US mail. It will be distributed to the patient during the pre-operative booking 
appointment. Placebo pills will also be ordered in similar fashion. Melatonin and placebo pills will be re-
packaged in the new blank pill bottles with a generic label with dosage instructions by the research 
coordinator. Only the unblinded research coordinator, will know which bottles correspond to the treatment 
group. 
5.1.2 Formulation, Appearance, Packaging, and Labeling 
Melatonin is a widely sold synthetic molecule in various forms including tablets, gummies and liquid. In 
the present study, the tablet version of the medication will be used at a dose of 5mg. It will be distributed 
to patients in a standard pill pack labelled as “Study Drug.” Patients will be informed that they will either 
be taking melatonin or a placebo pill with no chemical activity. Only the research staff involved in the 
randomization process will know if the patient is in the melatonin arm or the placebo arm. The placebo 
ingredients are Microcrystalline Cellulose, Silica, Gelatin, Titanium Dioxide, Red #3, and Blue #1. 
5.1.3 Product Storage and Stability 
The melatonin and placebo tablets will be stored in the Department of Orthopedic Surgery research 
offices at 380 2nd Avenue, 6th Floor, New York, NY, in a climate controlled office. As the product does not 
need to be refrigerated prior to being open there is no need for refrigeration storage. The average 
expiration date for a bottle of melatonin tablets is more than 1 year from purchase.  
5.1.4 Preparation 
There is no special preparation necessary for this product.  
5.1.5 Dosing and Administration 
There will be no special administration instructions given to patients, only that they should take one pill in 
the evening with water within 1 hour of bedtime each night for 14 days.  
5.1.6 Route of Administration 
Oral 
5.1.7 Duration of Therapy 
Patients will consume melatonin for 2 weeks.  

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5.1.8
Tracking of Dose
Patients will be encouraged to return the empty bottle at the 2 week postoperative visit.
5.2
Study Agent Accountability Procedures
The study agent, melatonin, and placebo will be stored at the Department of Orthopedic Surgery research 
office. When the patients are randomized to either arm of the study, the designated agent will be given to 
the patient at the preoperative visit. At the termination of the project any unused study agent will be 
destroyed on site in the trash. Any tablets or capsules will be mixed them all together with normal trash and 
placed in a sealed bag, then placed in a trash bin.  
6 Study Procedures and Schedule 
6.1 Study Procedures/Evaluations 
6.1.1 Study Specific Procedures 
 
Medical history- a patient’s medical history will be elicited during their pre-operative indication for 
surgery by their operative surgeon. This information will be then accessed via the EMR 
 
Medication history- current medications will be elicited during the patient’s pre-operative 
indication for surgery by their operative surgery. This information will then be accessed via the 
EMR 
 
Physical examination- the patient’s height and weight at each visit will be recorded, as well as a 
targeted physical musculoskeletal examination of the affected joint (ie hip for THA and knee for 
TKA). This information will then be accessed via the EMR 
 
Pre- and postoperative sleep survey,  
 
Survey on quality of sleep,  
 
Sleep diary 
o 
To be kept every day for the first 2 weeks 
 
VAS 
 
Opioid consumption will be measured based on in-patient pain medications given following 
surgery. This data will be pulled from Epic following discharge. 
6.1.2 Standard of Care Study Procedures 
The following procedures will be provided as standard of care:
1. Preoperative interview and evaluation of patients for indication for primary THA or TKA 
2. Preoperative health assessment and medical clearance 
3. THA or TKA 
4. Inpatient stay following procedure 
5. Post-operative follow-up appointments 
 
 
 
 
 
 
6.2 Study Schedule 
Procedure 
Screening/Visit 1
(SOC visit within -
3 months of 
surgery) 
Surgery 
Visit 2 (SOC visit within +2 
months of surgery) 

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Screening 
X 
(Research only)
 
 
Consent 
X 
(Research Only)
 
 
Medical History
X 
(SOC)
Surgical History 
X 
(SOC) 
 
 
Demographics
X 
(SOC)
Distribute 
medication 
 
X 
(Research 
Only) 
 
Collect pill bottle
X  
(Research Only)
Collect Adverse 
Events
 
 
X 
(Research Only)
Collect 
Questionnaires 
and peri-
operative data 
(in-patient opioid 
consumption, 
Epworth and 
Stanford 
sleepiness scale, 
VAS Pain Scale) 
X 
(Research Only) 
 
X  
(Research Only) 
Collect Sleep 
Diary
 
 
X  
(Research Only)
6.2.1 Screening  
Study subjects will be identified/recruited by all study investigators. Investigators will recruit subjects 
among their own patients who have been recommended to have a Total Hip or Knee Arthroplasty. 
Eligibility will be confirmed through a review of subject medical records. Investigators will reinforce with 
their patients that participation is voluntary, that they do not have to participate, and that their decision to 
not participate will not affect their care, now or in the future. During the course of the recruitment process, 
subjects will interact with all study personnel.  
 
With access granted by MCIT, Study team will access data/records in EPIC for patients identified by study 
investigators as meeting the study criteria. 
6.2.2 Enrollment/Baseline 
Enrollment/Baseline Visit (Visit 1) 
 
Review medical history to determine eligibility based on inclusion/exclusion criteria. 
 
Obtain informed consent of potential participant verified by signature on study informed consent 
form. 
 
Obtain and record vital signs, results of examinations, demographic information, medical history, 
medication history, alcohol and tobacco use history, and other assessments from the medical 
records. 
 
Record PROMIS – Sleep Disturbance 

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6.2.3
Intermediate Visits
TKA or THA Surgery 
 
Give patients the pill bottle with the study drug or placebo pill. 
Visit 2 (standard of care post-operatively visit within 2 months of surgery)  
 
Observe patient’s recovery from TJA surgery as per standard of care 
 
Record participant’s adherence to treatment program. 
 
Record patient standard sleepiness scale, PROMIS – Sleep Disturbance, VAS pain scores, 
collect sleep diary and opioid consumption. 
 
6.2.4 Withdrawal/Early Termination Visit 
If a patient wishes to terminate early no further procedures or interventions will be performed and the patient 
will be allowed to continue their pre- or post-operative care as per standard of care 
6.2.5  Unscheduled Visit 
Any unscheduled visits or contact from patients will be recorded in the EMR, which will be checked regularly 
by members of the research team for all study participants 
6.2.6 Precautionary Medications, Treatments, and Procedures 
There is no precautionary medications, treatments, and or procedures associated with the use of 
Melatonin  
6.3 Participant Access to Study Agent at Study Closure 
If a patient wishes to continue usage of melatonin after closure of the study they will be informed that it is 
a commercially available product they can obtain from any major retailer. 
7 Assessment of Safety 
7.1 Specification of Safety Parameters 
All safety parameters including patients vital signs and clinical examination as per standard of care will be 
recorded in their EMR.  
7.1.1 Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 

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7.1.2
Definition of Serious Adverse Events (SAE)
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
7.1.3 Definition of Unanticipated Problems (UP) 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
7.2 Classification of an Adverse Event 
7.2.1 Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity. 
 Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
 Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
 Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
7.2.2 Relationship to Study Agent 
The clinician’s assessment of an AE's relationship to study agent (drug, biologic, device) is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. If there 
is any doubt as to whether a clinical observation is an AE, the event should be reported. All AEs must 

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have their relationship to study agent assessed. In a clinical trial, the study product must always be 
suspect. To help assess, the following guidelines are used. 
 Related – The AE is known to occur with the study agent, there is a reasonable possibility that the 
study agent caused the AE, or there is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study agent and the AE. 
 Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event, there is no temporal relationship between the study agent and event onset, or 
an alternate etiology has been established. 
 
7.2.3 Expectedness 
The principal investigator, Joshua Rozell, MD will be responsible for determining whether an AE is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study agent. 
 
7.3 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All AEs 
including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate RF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system 
throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization.  
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  
7.3.1 Adverse Event Reporting 
Any AE’s encountered during the study will be identified by research personnel and brought to the 
attention of the PI. After investigation by the PI of the surrounding circumstances they will then be 
reported as quickly as possible, within 1 week, to the IRB, as indicated 
 

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7.3.2
Serious Adverse Event Reporting
Any SAE’s encountered during the study will be identified by research personnel and brought to the 
immediate attention of the PI. They will then be reported as quickly as possible, within 3 days, to the IRB 
7.3.3
Unanticipated Problem Reporting
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the site investigator’s responsibility to report UPs to their IRB. The UP report will include 
the following information: 
 Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
 A detailed description of the event, incident, experience, or outcome; 
 An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
 A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
 UPs that are SAEs will be reported to the IRB and to Dr. Rozell/lead PI within 1 week of the 
investigator becoming aware of the event. 
 Any other UP will be reported to the IRB and to Dr. Rozell/lead PI within 1 week of the investigator 
becoming aware of the problem. 
 All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and OHRP within 1 week 
of the IR’s receipt of the report of the problem from the investigator. 
 
7.3.4 Reporting of Pregnancy 
No pregnant patients will be included in the study. Any patient who becomes pregnant during the study 
will be removed from the study group.  
7.4 Reporting Procedures – Notifying Dr. Rozell
The study clinician will complete a SAE Form within the following timelines: 
 All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted to Dr. Rozell within 24 hours of site awareness. See Section 1, 
Key Roles for contact information. 
 Other SAEs regardless of relationship will be submitted to Dr. Rozell within 72 hours of site 
awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
Dr. Rozell and should be provided as soon as possible.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated event or the unanticipated problem in 
the form of a written narrative. This should include a copy of the completed Unanticipated Problem form, 
and any other diagnostic information that will assist the understanding of the event.  

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7.5
Safety Oversight
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above. 
Medical monitoring will include a regular assessment of the number and type of serious adverse events.  
PI will oversee data on an annual basis by creating reports from data entered into RedCap.  
 
8 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
 
 Monitoring for this study will be performed by the PI. 
 Monitoring will be on sight with frequent random checks of data. At conclusion of the study another 
independent member of the LOH arthroplasty research team not affiliated with the study will check 
all available data to ensure its validity 
 
Statistical Considerations 
8.1 Statistical Hypotheses 
 
Primary endpoint: The null hypothesis is that there is no difference between the melatonin and 
placebo group in the mean ESS score from days 1-14 postoperatively. The alternative hypothesis 
is that there is a difference between the melatonin and placebo group in the mean ESS score during 
any of these time points 
 
 
Secondary endpoints:  
o 
Hours of sleeping measured each day from days 1-14 for overnight sleep: The null hypothesis 
is that there is no difference between the melatonin and placebo group in the mean hours of 
sleeping at these time points. The alternative hypothesis is that there is a difference between 
the melatonin and placebo group in the mean hours of sleeping at these time points. Nighttime 
awakenings are those that require an additional dose of pain medication to go back to sleep.  
o 
Other secondary endpoints to be listed 
 
8.2 Sample Size and Power 
The overall study sample size is based on the primary endpoint of ESS measured at days 1-14. The 
MCID of the ESS is 2.65 and the SD is 5.3 based on previous literature21. We assume the MCID and ESS 
values are the same for both THA and TKA cohorts. 64 patients are needed in the control and 
intervention groups separately for a two-sided alpha = 0.05, 80% powered study based on an ANOVA for 
the comparison of the ESS at days 1-14 between the control and intervention group, which provides us a 
total of 128 patients for THA cohort and TKA cohort separately.  
 
8.3 Analysis Datasets 
All patients will be included in the efficacy analyses as randomized (intent-to-treat population). THA cohort 
and TKA cohort will be analyzed separately throughout.  

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8.4
Description of Statistical Methods
8.4.1
Analysis of the Primary Efficacy Endpoint
The primary outcome, the ESS score measured at days 1-14 postoperatively for each group, will be 
summarized using means, standard deviation, median and inter quartile ranges. In the main analysis, the 
ESS score of the control and intervention group in either THA or TKA cohort will be compared using 
repeated measures ANOVA. Significant tests will be two-sided at significant level at 0.05. 
The normality assumption of the primary efficacy outcome will be checked and strategies to transform the 
outcome variable will be considered. As a sensitivity analysis, the ANOVA will be replaced with the Wilcoxon 
rank sum test to ensure the robustness of the results. 
 
8.4.2
Analysis of the Secondary Efficacy Endpoints
The secondary endpoints include number of total hours of sleep, number of nighttime awakenings, and 
narcotic consumption.  
 
 
8.4.3 Safety Analyses 
AE’s will be recorded according to the Medical Dictionary for Regulatory Activities, counted once per 
individual occurrence, presented in terms of its severity and relationship to AE, and its start date, stop 
date, severity, relationship, outcome and duration will be reported. All AE’s will be ascertained via PI 
report.  
8.4.4 Adherence and Retention Analyses 
Adherence to the study will be analyzed by collecting the pill bottles at the first postoperative visit.  
8.4.5 Baseline Descriptive Statistics 
Baseline characteristics including age, sex, ASA class, BMI, past medical and surgical history will be 
recorded be summarized by melatonin and placebo group for THA and TKA cohort separately. Summary 
statistics will be used, where means and standard deviations will be reported for continuous variables, and 
count and proportion will be calculated for categorical variables. Inferential tests to assess differences in 
baseline characteristics of the groups will be performed using ANOVA or the Wilcoxon rank sum test if the 
normality assumption does not hold for continuous variables, and the Chi-square test for categorical 
variables. All tests will be two-sided with a significance level at 0.05. 
 
8.4.5.1 
Efficacy Review 
Planned interim analyses of the primary endpoint will not be performed.  
8.4.6 Additional Sub-Group Analyses 
Subgroup analyses of the primary and secondary endpoints will be done on the subgroups of THA vs TKA 
with ANOVA, and all other categorical variables will be analyzed using Fisher’s Exact Test. All tests will be 
two-sided with a significance level of 0.05. 
8.4.7 Multiple Comparison/Multiplicity 
Not applicable 
8.4.8 Tabulation of Individual Response Data 
Individual participant data will be listed by measure and time 

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. 
8.5 Measures to Minimize Bias
8.5.1
Enrollment/Randomization/Masking Procedures
Research assistants not involved in the study protocol will be responsible for maintaining the patient 
database and randomization algorithm. Treatment will begin on postoperative day zero. The control 
groups will receive 14 placebo pills. The treatment group will receive 14 pills of 5mg melatonin. Patients 
will begin taking a daily pill for 14 days postoperatively. They will continue to receive their selected 
treatment during their inpatient hospital stay. 
 
Block randomization will be done through RedCap to ensure equal distribution of intervention vs control 
subjects. The block size will be undisclosed. There will be no stratification based on age, gender, or 
surgery type. 
8.5.2 Evaluation of Success of Blinding 
Not applicable 
9 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source 
documents. If this is the case, it should be stated in this section what data will be collected on CRFs and 
what data will be collected from other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a space on the CRF is left 
blank because the procedure was not done or the question was not asked, write “N/D”. If the item is not 
applicable to the individual case, write “N/A”. All entries should be printed legibly in black ink. If any entry 
error has been made, to correct such an error, draw a single straight line through the incorrect entry and 
enter the correct data above it. All such changes must be initialed and dated. DO NOT ERASE OR 
WHITE OUT ERRORS. For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.). 
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 

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10 Quality Assurance and Quality Control
QC procedures will be implemented beginning with the data entry system and data QC checks that will be 
run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
11 Ethics/Protection of Human Subjects 
11.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
11.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
 
11.3 Informed Consent Process
11.3.1 Consent and Other Informational Documents Provided to Participants
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The following consent materials are submitted with this protocol: 
informed consent for participation 
11.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB-
approved and the participant will be asked to read and review the document.  
The informed consent process will take place at a pre-surgery clinic visit prior to the day of surgery or in 
the holding area on the day of surgery. If consenting occurs on the day of surgery, the study team will 
ensure that efforts are made so patients have enough time to make an informed decision to enroll in the 
study. A study coordinator, not associated with the surgery, will be the one to introduce the study to the 
patient in the holding area and patients will be given the opportunity to enroll in the study after the surgery 
is complete. 

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The Informed Consent Form (ICF) will be thoroughly explained in a private room with any and all 
questions addressed prior to signing the ICF. In the event additional time to make an inform decision is 
required, patient(s)/subject(s) will be able to take a copy of the ICF home for further review and 
discussion with their friends and family. During the course of the consenting process, subjects will interact 
with all study personnel. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. The participants may withdraw consent at any time throughout the 
course of the trial. A copy of the signed informed consent document will be given to the participants for 
their records. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The 
consent process, including the name of the individual obtaining consent, will be thoroughly documented in 
the subject’s research record. Any alteration to the standard consent process (e.g. use of a translator, 
consent document presented orally, etc.) and the justification for such alteration will likewise be 
documented.  
 
11.4 Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information  
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization. For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at NYU Langone Medical Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be identified 

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by a unique study identification number. The study data entry and study management systems used by 
clinical sites and by NYU Langone Medical Center research staff will be secured and password protected. 
At the end of the study, all study databases will be de-identified and archived at the NYU Langone 
Medical Center. 
 
 
12 Data Handling and Record Keeping
12.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained 
and captured in a progress note and maintained in the participant’s official electronic study record. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into a RedCap database, a encrypted, HIPAA-compliant data capture 
system managed by MCIT. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. Each site will have access to its 
identifiable data. Only de-identified data will be passed between institutions. 
 
12.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication. 
12.3 Protocol Deviations
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
 
These practices are consistent with ICH E6: 
 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
 5.1 Quality Assurance and Quality Control, section 5.1.1 
 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations 
within 7 working days of identification of the protocol deviation, or within 7 working days of the scheduled 
protocol-required activity. 

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All protocol deviations must be addressed in study source documents, reported to the IRB and Lead PI 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. Further details about the handling of 
protocol deviations will be included in the MOP. 
12.4 Publication and Data Sharing Policy 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s responsibility 
to register the trial in an acceptable registry, so the research results may be considered for publication in 
ICMJE member journals. The ICMJE does not review specific studies to determine whether registration is 
necessary; instead, the committee recommends that researchers who have questions about the need to 
register err on the side of registration or consult the editorial office of the journal in which they wish to 
publish. 
 
13 Study Finances 
13.1 Funding Source 
This study is funded by the NYU Department of Orthopedic surgery specifically via the established 
William Jaffe grant for resident research.  
13.2 Costs to the Participant
The participant will incur no costs for participation in the study
13.3 Participant Reimbursements or Payments
Participants will not be given any reimbursements or payments for participation in the study 
14 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. The study leadership has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a mechanism 
for the management of all reported dualities of interest.  
 

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Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU 
Langone Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. All 
NYULMC investigators will follow the applicable conflict of interest policies. 
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