Conditions: Prolonged Grief Disorder
Keywords: Naltrexone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
This is a study to see how effective oral naltrexone is as treatment for prolonged grief disorder (PGD). Participants will take their assigned medication for 8 weeks, with monthly visits to assess symptom severity, social connectedness, and adverse reactions.

Detailed description:

Arms:
arm 1: 24 randomized patients will take placebo daily for 8 weeks. arm 2: 24 randomized patients will take naltrexone daily for 8 weeks

Interventions: intervention 1: Naltrexone HCl 50 MG Oral Tablet intervention 2: Placebo
Intervention descriptions: intervention 1: Generic, oral tablet. intervention 2: Composed of filler material and encapsulated to appear identical to naltrexone.

Protocol document:
Prot_SAP_000.pdf: 
TITLE: Naltrexone Treatment for Prolonged Grief Disorder: A Pilot Study 
NCT Number: NCT04547985 
Date: 6/18/2021 
 


 
 
  
Page # i 
 
 
TITLE: Naltrexone Treatment for Prolonged Grief Disorder: A Pilot Study 
 
IRB Protocol #: 20-04021873 
IND/IDE #: IND Exempt 
Version Date: 6/18/21 
Funding Source(s): NCI/NIH 
 
Principal Investigator: 
 
Holly G. Prigerson, PhD 
 
 
420 E 70Pth
P Street, 3Prd
P Floor, Room 321 
617-459-3304 
hgp2001@med.cornell.edu 
 
Co-Investigators: 
 
James Gang, BA 
267-314-1552 
jmg2016@med.cornell.edu 
 
 
 
Jonathan Avery, MD  
525 E 68Pth
P Street, Box 140, Office 1187 
212-746-3738 
joa9070@med.cornell.edu 
 
James Kocsis, MD 
525 E 68th Street 
212-746-5913 
jhk2002@med.cornell.edu 
 
Paul K. Maciejewski, PhD 
420 E 70th Street, 3rd Floor 
212-746-2229 
pam2056@med.cornell.edu 
 
Naomi Woubeshet, BA 
525 E. 68th St., 14th Floor Box 39 
646-962-7162 
naw4001@med.cornell.edu 
 
Statistician: 
Medical Monitor: 
 
Cici Jiehui Xi 
Janna Gordon-Elliott, MD 
 
420 E 70Pth
P Street, 3Prd
P Floor 
525 E. 68th Street, Box 140 
 
212-746-9262 
212-756-3630 
 
jix2013@med.cornell.edu 
jsg2005@med.cornell.edu 
 
 
Participating Sites: NYP-WCM; Dr. Holly G. Prigerson; 617-459-3304 
 


Protocol # 20-04021873 
6/18/21 
 
Page # ii 
 
Table of Contents 
2TCONFIDENTIALITY STATEMENT2T ..................................................................................... VI 
2TLIST OF ABBREVIATIONS2T ............................................................................................... VII 
2T1. PROTOCOL SUMMARY2T .................................................................................................. 1 
2T1.12T 
2TSchema2T ...................................................................................................................... 5 
2T1.2T 
2TStudy Objectives and End Points2T ......................................................................... 6 
2T1.2.1 2T 
2TPrimary Objectives2T ........................................................................................... 6 
2T1.2.2 2T 
2TSecondary Objectives2T ...................................................................................... 6 
2T1.2.3 2T 
2TExploratory Objectives2T .................................................................................... 6 
2T1.2.42T 
2TPrimary Endpoints2T ............................................................................................ 6 
2T1.2.52T 
2TSecondary Endpoints2T ...................................................................................... 6 
2T1.2.62T 
2TExploratory Endpoints2T ..................................................................................... 7 
2T1.2.72T 
2TSafety Endpoints2T .............................................................................................. 7 
2T2. BACKGROUND2T ................................................................................................................ 8 
2T2.12T 
2TDisease2T ...................................................................................................................... 8 
2T2.2T 
2TInvestigational Agent2T .............................................................................................. 8 
2T2.32T 
2TRationale2T ................................................................................................................. 10 
2T2.42T 
2T Risk/Benefit Assessment2T .................................................................................... 11 
2T2.4.12T 
2TKnown Potential Risks2T ................................................................................... 11 
2T2.4.2T 
2TKnown Potential Benefits2T .............................................................................. 12 
2T2.4.32T 
2TAssessment of Potential Risks and Benefits2T ............................................. 12 
2T2.52T 
2TCorrelative Studies Background2T ......................................................................... 13 
2T3. STUDY DESIGN2T ............................................................................................................. 13 
2T3.12T 
2TOverall Design2T ........................................................................................................ 13 
2T3.2T 
2TScientific Rationale for Study Design2T ................................................................ 14 
2T3.32T 
2TJustification for Dose2T ............................................................................................ 14 
2T3.42T 
2TEnd of Study Definition2T ........................................................................................ 14 
2T4. SUBJECT SELECTION2T .................................................................................................. 14 
2T4.12T 
2TStudy Population2T ................................................................................................... 14 
2T4.2T 
2TInclusion Criteria2T ................................................................................................... 14 
2T4.32T 
2TExclusion Criteria2T .................................................................................................. 15 
2T4.42T 
2TLifestyle Considerations2T ...................................................................................... 15 
2T4.52T 
2TScreen Failures2T ...................................................................................................... 15 
2T4.62T 
2TStrategies for Recruitment and Retention2T ......................................................... 16 
2T5. REGISTRATION PROCEDURES2T .................................................................................. 16 
2T5.12T 
2TSubject Registration (WCM only)2T ........................................................................ 16 
2T5.2 Subject Registration (Sub-sites)2T ............................................................................. 17 


Protocol # 20-04021873 
6/18/21 
 
Page # iii 
 
2T6. STUDY PROCEDURES2T ................................................................................................. 17 
2T6.12T 
2TSchedule of Assessments2T ................................................................................... 17 
2T6.1.12T 
2TPhone Screen2T .................................................................................................. 17 
2T6.1.2T 
2TTreatment Phase2T ............................................................................................. 18 
2T6.1.2.12T 
2TVisit 1 (baseline; Day 1)2T .............................................................................. 18 
2T6.1.2.2T 
2TVisit 2 (+28 days)2T ......................................................................................... 18 
2T6.1.32T 
2TFollow-up Phase (+28 days) – administered via REDcap2T ........................ 19 
2T7. STUDY INTERVENTION2T ................................................................................................ 19 
2T7.12T 
2TStudy Intervention/Device Description2T .............................................................. 19 
2T7.2T 
2TAvailability2T .............................................................................................................. 19 
2T7.32T 
2TAcquisition and Accountability2T ........................................................................... 19 
2T7.42T 
2TFormulation, Appearance, Packaging, and Labeling2T ...................................... 20 
2T7.52T 
2TProduct Storage and Stability2T ............................................................................. 20 
2T7.62T 
2TPreparation2T ............................................................................................................. 20 
2T7.72T 
2TDosing and Administration2T .................................................................................. 20 
2T7.7.12T 
2TDosing Delays/Dose Modifications2T .............................................................. 21 
2T7.82T 
2TGeneral Concomitant Medication and Supportive Care Guidelines2T ............. 21 
2T7.92T 
2TDuration of Therapy and Criteria for Removal from Study2T ............................ 21 
2T7.10 Duration of Follow Up2T ............................................................................................. 21 
2T7.11 Measures to Minimize Bias: Randomization and Blinding2T ............................... 21 
2T7.12 Study Intervention/Follow-up Compliance2T ......................................................... 23 
2T8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL2T ............................................................................... 23 
2T8.12T 
2TDiscontinuation of Study Intervention2T ............................................................... 23 
2T8.2T 
2TParticipant Discontinuation/Withdrawal from the Study2T ................................ 23 
2T8.32T 
2TLost to Follow Up2T ................................................................................................... 24 
2T9. CORRELATIVE/SPECIAL STUDIES2T ............................................................................ 24 
2TNot applicable2T ............................................................................................................... 24 
2T10. MEASUREMENT OF EFFECT2T .................................................................................... 24 
2T10.1 Response Criteria2T .................................................................................................... 24 
2T10.2 Duration of Response2T ............................................................................................. 24 
2T10.3 Progression-Free Survival2T ..................................................................................... 25 
2T10.4 Other Response Parameters2T ................................................................................. 25 
2T11. DATA REPORTING / REGULATORY CONSIDERATIONS2T ..................................... 25 
2T11.1 Data Collection2T ........................................................................................................ 25 
2T11.1.1 REDCap2T .............................................................................................................. 25 
2T11.2 Regulatory Considerations2T .................................................................................... 25 
2T11.2.1 Institutional Review Board/Ethics Committee Approval2T ........................... 25 
2T11.2.2 Ethical Conduct of the Study2T ......................................................................... 26 


Protocol # 20-04021873 
6/18/21 
 
Page # iv 
 
2T11.2.3 Informed Consent2T ............................................................................................. 26 
2T11.2.4 Compliance with Trial Registration and Results Posting Requirements2T 26 
2T11.2.5 Record Retention2T ............................................................................................. 26 
2T12. STATISTICAL CONSIDERATIONS2T ............................................................................ 27 
2T12.1 Study Design/Endpoints2T ........................................................................................ 27 
2T12.2 Sample Size/Accrual Rate2T ...................................................................................... 27 
2T12.3 Stratification Factors2T .............................................................................................. 27 
2TNo stratification factor is applicable to this single-site pilot study.2T ....................... 28 
2T12.4 Analysis of Endpoints2T ............................................................................................ 28 
2T12.4.12T 
2TAnalysis of Primary Endpoints2T ................................................................. 28 
2T12.4.2T 
2TAnalysis of Secondary Endpoints2T ............................................................ 28 
2T12.5 Interim Analysis2T ....................................................................................................... 28 
2T12.6 Reporting and Exclusions2T ..................................................................................... 29 
2T12.6.12T 
2TEvaluation of Toxicity2T ................................................................................. 29 
2T12.6.2T 
2TEvaluation of Response2T ............................................................................. 29 
2T13. ADVERSE EVENT REPORTING REQUIREMENTS2T ................................................. 29 
2T13.1 Adverse Event Definition2T ....................................................................................... 29 
2T13.1.12T 
2TInvestigational Agent (Expected Adverse Events)2T ................................ 29 
2T13.1.2T 
2TAdverse Event Characteristics and Related Attributions2T .................... 29 
2T13.1.32T 
2TRecording of Adverse Events2T ................................................................... 30 
2T13.1.42T 
2TReporting of AE to WCM IRB2T .................................................................... 30 
2T13.1.52T 
2TReporting Events to Participants2T ............................................................. 30 
2T13.1.62T 
2TEvents of Special Interest2T .......................................................................... 30 
2T13.1.72T 
2TReporting of Pregnancy2T ............................................................................. 30 
2T13.2 Definition of SAE2T ..................................................................................................... 31 
2T13.2.12T 
2TReporting of SAE to IRB2T ............................................................................ 31 
2T13.2.2T 
2TReporting of SAE to FDA2T ........................................................................... 31 
2T13.2.32T 
2TReporting of SAE to Doyle’s Pharmacy2T .................................................. 31 
2T13.3 AE/SAE Follow Up2T ................................................................................................... 31 
2T13.4 Time Period and Frequency for Event Assessment and Follow Up2T ............... 32 
2T14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS2T32 
2T14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO)2T ......................................................................................................................... 32 
2T14.1.2T 
2TUnanticipated Problem Reporting2T ............................................................ 33 
2T15. DATA AND SAFETY MONITORING PLAN (DSMP)2T ................................................. 33 
2T16. REFERENCES2T .............................................................................................................. 35 
 
 
 
 


Protocol # 20-04021873 
6/18/21 
 
Page # v 
 
 
Statement of Compliance 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (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.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol # 20-04021873 
6/18/21 
 
Page # vi 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others without 
written authorization from WCM, unless disclosure on ClinicalTrials.gov is federally required. 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol # 20-04021873 
6/18/21 
 
Page # vii 
 
List of Abbreviations 
 
AE 
ACE 
ALT 
AST 
C-SSRS 
Adverse Event 
Acute Care of the Elderly 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Columbia-Suicide Severity Rating Scale 
CFR 
COMBINE 
CONSORT 
COVID-19 
Code of Federal Regulations 
Combined Pharmacotherapies and Behavioral Interventions 
Consolidated Standards of Reporting Trials 
Coronavirus Disease 2019 
CRF 
CTCAE 
Case Report Form 
Common Terminology Criteria for Adverse Events 
CTSC 
DARF 
DSM 
Clinical Translational Science Center  
Drug Accountability Record Form 
Diagnostic and Statistical Manual of Mental Disorders 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
HCl 
HDPE 
Good Clinical Practice 
Hydrochloride 
High-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HUD 
ICD 
Humanitarian Use Device  
International Classification of Diseases 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption  
IND 
IOS 
Investigational New Drug 
Inclusion of the Other in the Self 
IRB 
ISEL 
LFT 
MDD 
MICU 
NIH 
NYP 
OHRP 
PO 
Institutional Review Board 
Interpersonal Support Evaluation List 
Liver Function Tests 
Major Depressive Disorder 
Medical Intensive Care Unit 
National Institute of Health 
NewYork-Presbyterian 
Office for Human Research Protections 
Per os (by mouth) 


Protocol # 20-04021873 
6/18/21 
 
Page # viii 
 
PG-13-R 
PGD 
Prolonged Grief Intensity Scale - Revised 
Prolonged Grief Disorder 
PHI 
Protected Health Information 
PI 
PTSD 
RCT 
Principal Investigator 
Post-traumatic Stress Disorder 
Randomized Control Trial 
REDCap 
Research Electronic Data Capture 
SAE 
SCS 
SCIP 
SIQ 
SD 
SSRI 
Serious Adverse Event 
Social Connectedness Survey 
Structured Clinical Interview for PGD 
Standard Deviation 
Social Integration Questionnaire 
Selective Serotonin Reuptake Inhibitor 
SUSAR 
TCA 
USP 
Suspected Unexpected Serious Adverse Reaction  
Tricyclic Antidepressant 
United States Pharmacopeia 
UIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
WCM 
 
Weill Cornell Medicine 
 


Protocol # 20-04021873 
 
 
 
6/15/20
 
  
Page # 1 
 
1. Protocol Summary 
 
Full Title:  
 
 
 
Naltrexone Treatment for Prolonged Grief Disorder: A Pilot Study 
Short Title: 
 
 
 
Naltrexone Use for PGD 
Clinical Phase: 
 
 
IV 
Principal Investigator:  
Holly Prigerson, PhD 
Study Description:   
This is a randomized, placebo-controlled pilot study to establish 
the efficacy of using oral naltrexone as a pharmacological 
treatment for prolonged grief disorder (PGD). Participants will take 
their assigned medication for 8 weeks, with monthly visits to 
assess symptom severity, social connectedness, and adverse 
reactions.   
Sample Size: 
 
NRtotal 
R= 48: NRnaltrexone
R = 24, NRcontrol
R = 24 
Enrollment: 
 
This study will enroll 48 subjects and screen up to 80 subjects. 
Study Population: 
 
Bereaved individuals meeting criteria for PGD who are > 18 years 
old.  
Enrollment Period:  
12 months 
Study Design: 
 
This study will be a triple-blinded, randomized, placebo-controlled 
trial with a sample size of 48 participants. Monthly clinic visits will 
take approximately 1 hour to complete. Weekly surveys of PG-13-
R will take approximately 15 minutes to complete. 
Description of Sites/  
Facilities Enrolling 
Participants: 
 
Enrollment will take place at various NYP-WCM locations via 
EPIC review, flyers, referrals, and in-person recruitment.  
Study Duration: 
 
June 1, 2020 – August 31, 2021 
Participant Duration: 
12 weeks 
Study Agent/Device Name  
Intervention Description: 
Naltrexone 50 mg PO daily for 8 weeks 
 
Primary Objective: 
To determine the efficacy of naltrexone in reducing PGD 
symptoms compared to placebo. 
 
Secondary Objectives: 
To evaluate the effects of naltrexone on social closeness with both 
the decreased (source of bereavement) and the living. 
Exploratory Objectives: 
 
 
• 
To evaluate the effects of naltrexone on social integration and social connectedness. 
• 
To evaluate the effects of naltrexone on suicidal thoughts and behaviors. 
• 
To evaluate the effects of naltrexone on health behaviors (e.g. alcohol and tobacco use, 
sleep, food consumption). 
• 
To evaluate differences between outcomes of COVID-19-related deaths and other 
causes of death. 
 
Primary Endpoints: 
PG-13-R (Grief Intensity Scale): PGD symptoms will be 
measured by using PG-13-R, a self-rated scale consisting of 13 


Protocol # 20-04021873 
6/18/21 
 
Page # 2 
 
items:3 yes/no questions, and 10 Likert-scale questions. This 5-
point Likert-type of measurement tool evaluates the intensity and 
severity of the PGD. It was shown that PG-13-R has good internal 
consistency among three study samples (α = .83-.93) (Prigerson 
et al. 2021). A symptom threshold score of 30 optimized 
agreement with meeting DSM symptom criteria for PGD (kappa 
≥0.70 across the datasets) (Prigerson et al. 2021). Participants will 
be sent weekly PG-13-R surveys through email via REDcap.  
 
 
Structured Clinical Interview for PGD (SCIP): This structured 
clinical interview is adapted to the DSM-5 criteria for PGD. 
Interviewers will be trained to standard which will be a κ > 0.8 
agreement between trainee and trainer. Participants will be 
interviewed at every monthly visit. 
 
Secondary Endpoints: 
Inclusion of the Other in the Self (IOS) Scale: The IOS is a self-
reported pictorial tool used to measure the subjectively perceived 
closeness of a relationship. The tool asks respondents to select 
one of seven pairs of increasingly overlapping circles that best 
represents their relationship with another, with more overlap 
signifying a closer relationship. This scale possesses good 
reliability, with (α = .93) for the entire sample, (α = .87) for family, 
(α = .92) for friendship, and (α = .95) for romantic relationships. 
Test-retest reliability shows similar findings, with (α = .83) for the 
entire sample, (α = .85) for family, (α = .86) for friendship, and (α = 
.85) for romantic relationships (Aron et al., 1992). This scale will 
be administered monthly at every visit, as well as at follow-up. 
 
 
 
Exploratory Endpoints: 
Social Integration Questionnaire (SIQ): Social Integration 
Questionnaire is a 10-item self-reported scale adapted from The 
General Social Survey distributed by the National Opinion 
Research Center. The participants rate the social activities they 
engage in and the degree of involvement of each (Tsai & 
Rosenheck, 2012). Questions will assess feelings and thoughts 
while engaged in these activities to gauge the study participant’s 
level of social integration. Measuring social integration is important 
as we hypothesize that detachment from the decreased is a 
necessary first step towards being able to socially connect with 
others. In addition, social support can influence the bereavement 
process and thus PG-13-R scores. This scale will be administered 
monthly at every visit, as well as at follow-up. 
 
Interpersonal Support Evaluation List (ISEL): Interpersonal 
Support Evaluation List is a 40-item self-reported interpersonal 
support evaluation scale (Cohen et al., 1985). The version used in 
this study is a shortened 16-item version adapted from the Yale 
Bereavement Study. The participants rate each item regarding 
how true or false they believe it is on a 4-point scale ranging from 


Protocol # 20-04021873 
6/18/21 
 
Page # 3 
 
“Definitely True” to “Definitely False.” This survey will be 
administered monthly at every visit, as well as at follow-up. 
 
Social Connectedness Survey (SCS): We have developed a 
brief self-reported survey for this study consisting of questions 
including but not limited to: assessing how much participants are 
socializing, who they are socializing with, and how enjoyable 
socializing is. This survey will be administered monthly at every 
visit, as well as at follow-up. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS): The 
CSSRS scale is a validated scale to assess suicidal behavior and 
ideation (Posner et al., 2011). It will be administered monthly by a 
trained rater at the site of all visits. This study will use 2 versions 
of the C-SSRS. At the Screening Visit, the baseline/screening 
version will be completed; for all subsequent visits the “Since Last 
Visit” version of the C-SSRS will be administered. The “Since Last 
Visit” version will also be administered online for follow-up. 
 
If the subject screens positive for serious suicidal intent with or 
without a plan, they will be immediately excluded from the study, 
and we will have a licensed mental health professional (e.g., 
psychiatrist, psychologist) more fully evaluate suicidality and make 
arrangements for them to get to a local hospital Emergency Room 
if serious risk is imminent. If not at imminent risk but passive 
suicidal ideation was endorsed (e.g. only endorsing item 1), we 
will offer them referral to a licensed mental health professional. 
 
Health Behaviors: Smoking history, alcohol history, health 
perception, and health promoting behaviors will be measured 
using the standard self-reported questionnaires validated in Yale 
Bereavement Study Measures monthly at every visit, as well as at 
follow-up. 
 
Safety Endpoints:  
Review of Side-Effects: At the 2Pnd
P and 3Prd
P visits, participants will 
be asked a nonspecific question (e.g. Have you notice any new 
side-effects since your last visit?) to assess whether any side-
effects have been experienced since Day 1. Side-effects will be 
recorded on a REDCap Case Report Form (CRF) and reported to 
the independent medical monitor. 
 
Laboratory tests: Laboratory tests are to screen participants for 
exclusion criteria and assess potential adverse effects. Blood 
samples will be obtained at all three-monthly visits. Laboratory 
tests will assess liver function tests (for bilirubin, gamma glutamyl 
transpeptidase, alkaline phosphatase, aspartate transaminase, 
alanine aminotransferase, albumin and protein). Similarly, 
quantitative urine pregnancy tests will be obtained at all three-
monthly visits and used to determine pregnancy status. The 


Protocol # 20-04021873 
6/18/21 
 
Page # 4 
 
monthly frequency of testing has been deemed sufficient by our 
physician co-investigators. 
 
One designated member of the study staff will review laboratory 
tests results and report any significant findings to the PI, as 
outlined in section 7.11. 
 
 
 
 
 
 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 5 
 
1.1 Schema 
 
 
 
Prior to 
Enrollment 
 
 
Visit 1 
Day 0/Wk 1 
 
 
 
 
  
 
 
 
 
 
Visit 1 
Day 0 cont’d 
 
 
 
 
 
Visit 2  
Day 28/Wk 4 
 
 
 
 
 
Visit 3 
Day 56/Wk 8 
 
 
 
 
 
 
Follow-up 
Day 84/Wk 12 
 
 
 
 
 
 
Total N = 80: Phone screen potential participants by inclusion and exclusion criteria 
Obtain ICF 
Screen: SCIP, C-SSRS, Medical History, Review of Medications 
Follow-up assessments (refer to section 6.1) 
Count tablets 
Take blood sample 
 
Follow-up assessments (refer to section 
6.1) 
 
Arm 2 (Placebo) 
N =24 
Arm 1 (Naltrexone) 
N = 24 
Follow-up assessments (refer to section 6.1) 
Count tablets 
Take blood sample 
Randomize 
Perform baseline assessments (refer to section 6.1)  
Take blood sample  
Dispense 8-week supply of medication  


Protocol # 20-04021873 
6/18/21 
 
Page # 6 
 
1.2 Study Objectives and End Points 
 
 
1.2.1  Primary Objectives  
 
To determine the efficacy of naltrexone in reducing PGD symptoms compared to 
placebo. 
 
1.2.2  Secondary Objectives  
 
To evaluate the effects of naltrexone on social closeness with both the decreased 
(source of bereavement) and the living. 
 
1.2.3  Exploratory Objectives 
 
 
 
o To evaluate the effects of naltrexone on social integration and social 
connectedness. 
o To evaluate the effects of naltrexone on suicidal thoughts and behaviors. 
o To evaluate the effects of naltrexone on health behaviors (e.g. alcohol and 
tobacco use, sleep, food consumption). 
o To evaluate differences between outcomes of COVID-19-related deaths and 
other causes of death. 
 
 
1.2.4 Primary Endpoints 
 
PG-13-R (Grief Intensity Scale): PGD symptoms will be measured by using PG-13-R, a 
self-rated scale consisting of 13 items:3 yes/no questions, and 10 Likert-scale questions. 
This 5-point Likert-type of measurement tool evaluates the intensity and severity of the 
PGD. It was shown that PG-13-R has good internal consistency among three study 
samples (α = .83-.93) (Prigerson et al. 2021). A symptom threshold score of 30 
optimized agreement with meeting DSM symptom criteria for PGD (kappa ≥0.70 across 
the datasets) (Prigerson et al. 2021). Participants will be sent weekly PG-13-R surveys 
through email via REDcap.   
 
Structured Clinical Interview for PGD (SCIP): This structured clinical interview is 
adapted to the DSM-5-TR criteria for PGD. Interviewers will be trained to standard which 
will be a κ > 0.8 agreement between trainee and trainer. Participants will be interviewed 
at every monthly visit. 
 
1.2.5 Secondary Endpoints 
 
 
Inclusion of the Other in the Self (IOS) Scale: The IOS is a self-reported pictorial tool 
use to measure the subjectively perceived closeness of a relationship. The tool asks 
respondents to select one of seven pairs of increasingly overlapping circles that best 
represents their relationship with another, with more overlap signifying a closer 
relationship. This scale possesses good reliability, with (α = .93) for the entire sample, (α 
= .87) for family, (α = .92) for friendship, and (α = .95) for romantic relationships. Test-
retest reliability shows similar findings, with (α = .83) for the entire sample, (α = .85) for 
family, (α = .86) for friendship, and (α = .85) for romantic relationships (Aron et al., 
1992). This scale will be administered monthly at every visit, as well as at follow-up. 


Protocol # 20-04021873 
6/18/21 
 
Page # 7 
 
 
 
1.2.6 Exploratory Endpoints 
 
 
Social Integration Questionnaire (SIQ): Social Integration Questionnaire is a 10-item 
self-reported scale adapted from The General Social Survey distributed by the National 
Opinion Research Center (NORC). The participants rate the social activities they engage 
in and the degree of involvement of each (Tsai & Rosenheck, 2012). Questions will 
assess feelings and thoughts while engaged in these activities to gauge the study 
participant’s level of social integration. Measuring social integration is important as we 
hypothesize that detachment from the decreased is a necessary first step towards being 
able to socially connect with others. In addition, social support can influence the 
bereavement process and thus PG-13-R scores. This scale will be administered monthly 
at every visit, as well as at follow-up. 
 
 
Interpersonal Support Evaluation List (ISEL): Interpersonal Support Evaluation List is 
a 40-item self-reported interpersonal support evaluation scale (Cohen et al., 1985). The 
version used in this study is a shortened 16-item version adapted from the Yale 
Bereavement Study. The participants rate each item regarding how true or false they 
believe it is on a 4-point scale ranging from “Definitely True” to “Definitely False.” This 
survey will be administered monthly at every visit, as well as at follow-up. 
 
 
Social Connectedness Survey (SCS): We have developed a brief self-reported survey 
for this study consisting of questions including but not limited to: assessing how much 
participants are socializing, who they are socializing with, and how enjoyable socializing 
is. This survey will be administered monthly at every visit, as well as at follow-up. 
 
Columbia Severity Rating Scale (C-SSRS): The CSSRS scale is a validated scale to 
assess suicidal behavior and ideation (Posner et al., 2011). It will be administered 
monthly by a trained rater at the site of all visits. This study will use 2 versions of the C-
SSRS. At the Screening Visit, the baseline/screening version will be completed; for all 
subsequent visits the “Since Last Visit” version of the C-SSRS will be administered. The 
“Since Last Visit” version will also be administered online for follow-up. 
 
If the subject screens positive for serious suicidal intent with or without a plan, we will 
have a licensed mental health professional (e.g., psychiatrist, psychologist) more fully 
evaluate suicidality and make arrangements for them to get to a local hospital 
Emergency Room if serious risk is imminent. If not at imminent risk but suicidal ideation 
was endorsed, we will refer them to a licensed mental health professional. 
 
Health Behaviors: Smoking history, alcohol history, health perception, and health 
promoting behaviors will be measured using the standard self-reported questionnaires 
validated in Yale Bereavement Study Measures monthly at every visit, as well as at 
follow-up. 
 
1.2.7 Safety Endpoints 
 
Review of Side-Effects: At the 2Pnd
P and 3Prd
P visits, participants will be asked a nonspecific 
question (e.g. Have you notice any new side-effects since your last visit?) to assess 
whether any side-effects have been experienced since Day 1. Side-effects will be 
recorded on a REDCap Case Report Form (CRF) and reported to the independent 


Protocol # 20-04021873 
6/18/21 
 
Page # 8 
 
medical monitor. 
 
Laboratory tests: Laboratory tests are to screen participants for exclusion criteria and 
assess potential adverse effects. Blood samples will be obtained at all three-monthly 
visits. Laboratory tests include liver function tests (for bilirubin, gamma glutamyl 
transpeptidase, alkaline phosphatase, aspartate transaminase, alanine 
aminotransferase, albumin and protein). Similarly, quantitative urine pregnancy tests will 
be obtained at all three-monthly visits and used to determine pregnancy status. The 
monthly frequency of testing has been deemed sufficient by our physician co-
investigators. 
 
One designated member of the study staff will review laboratory tests results and report 
any significant findings to the PI, as outlined in section 7.11. 
 
2. Background 
 
UAll text within quotation marks are taken directly from the FDA package insert. 
 
2.1 Disease 
 
The recent inclusion of PGD in the ICD-11 and DSM-5-TR has been a catalyst for research 
to advance understanding and treatment of this newly recognized mental disorder. PGD, a 
maladaptive response to the death of a loved one, is characterized by persistent yearning 
for the deceased and disabling symptoms such as emotional numbness, a sense of disbelief 
about the death, identity disruption, and an inability to move on and find meaning in life in 
the absence of the deceased. When these symptoms are functionally impairing and severe 
at 12 months post-loss, a person can now be diagnosed as meeting criteria for PGD.   
 
2.2 Investigational Agent 
 
“Naltrexone is a pure opioid antagonist. It markedly attenuates or completely blocks, 
reversibly, the subjective effects of intravenously administered opioids…Naltrexone has few, 
if any, intrinsic actions besides its opioid blocking properties… The administration of 
Naltrexone is not associated with the development of tolerance or dependence…Clinical 
studies indicate that 50 mg of Naltrexone will block the pharmacologic effects of 25 mg of 
intravenously administered heroin for periods as long as 24 hours… The mechanism of 
action of Naltrexone in alcoholism is not understood; however, involvement of the 
endogenous opioid system is suggested by preclinical data…Naltrexone is not aversive 
therapy and does not cause a disulfiram-like reaction either as a result of opiate use or 
ethanol ingestion. 
 
Although well absorbed orally, naltrexone is subject to significant first pass metabolism with 
oral bioavailability estimates ranging from 5 to 40%. The activity of naltrexone is believed to 
be due to both parent and the 6ß-naltrexol metabolite. Both parent drug and metabolites are 
excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of 
unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a 
minor elimination pathway. The mean elimination half-life (T-1/2) values for naltrexone and 
6-ß-naltrexol are 4 hours and 13 hours, respectively. Naltrexone and 6-ß-naltrexol are dose 
proportional in terms of AUC and Cmax over the range of 50 to 200 mg and do not 
accumulate after 100 mg daily doses. 


Protocol # 20-04021873 
6/18/21 
 
Page # 9 
 
 
Following oral administration, naltrexone undergoes rapid and nearly complete absorption 
with approximately 96% of the dose absorbed from the gastrointestinal tract. Peak plasma 
levels of both naltrexone and 6-ß-naltrexol occur within one hour of dosing. 
 
The volume of distribution for naltrexone following intravenous administration is estimated to 
be 1350 liters. In vitro tests with human plasma show naltrexone to be 21% bound to plasma 
proteins over the therapeutic dose range. 
 
The systemic clearance (after intravenous administration) of naltrexone is ~3.5 L/min, which 
exceeds liver blood flow (~1.2 L/min). This suggests both that naltrexone is a highly 
extracted drug (>98% metabolized) and that extrahepatic sites of drug metabolism exist. 
The major metabolite of naltrexone is 6-ß-naltrexol. Two other minor metabolites are 2-
hydroxy-3-methoxy-6-ß-naltrexol and 2-hydroxy-3-methyl-naltrexone. Naltrexone and its 
metabolites are also conjugated to form additional metabolic products. 
 
The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal 
elimination is primarily by glomerular filtration. In comparison, the renal clearance for 6ß-
naltrexol ranges from 230 to 369 mL/min, suggesting an additional renal tubular secretory 
mechanism. The urinary excretion of unchanged naltrexone accounts for less than 2% of an 
oral dose; urinary excretion of unchanged and conjugated 6-ß-naltrexol accounts for 43% of 
an oral dose. The pharmacokinetic profile of naltrexone suggests that naltrexone and its 
metabolites may undergo enterohepatic recycling. 
 
During two randomized, double-blind placebo-controlled 12-week trials to evaluate the 
efficacy of Naltrexone as an adjunctive treatment of alcohol dependence, most patients 
tolerated Naltrexone well. In these studies, a total of 93 patients received Naltrexone at a 
dose of 50 mg once daily. Five of these patients discontinued Naltrexone because of 
nausea. No serious adverse events were reported during these two trials. 
 
While extensive clinical studies evaluating the use of Naltrexone in detoxified, formerly 
opioid-dependent individuals failed to identify any single, serious untoward risk of Naltrexone 
use, placebo-controlled studies employing up to fivefold higher doses of Naltrexone (up to 
300 mg per day) than that recommended for use in opiate receptor blockade have shown 
that naltrexone causes hepatocellular injury in a substantial proportion of patients exposed 
at higher doses 
 
Aside from this finding, and the risk of precipitated opioid withdrawal, available evidence 
does not incriminate naltrexone, used at any dose, as a cause of any other serious adverse 
reaction for the patient who is "opioid-free." It is critical to recognize that naltrexone can 
precipitate or exacerbate abstinence signs and symptoms in any individual who is not 
completely free of exogenous opioids. 
 
A dose of 50 mg once daily is recommended for most patients. The placebo-controlled 
studies that demonstrated the efficacy of naltrexone as an adjunctive treatment of 
alcoholism used a dose regimen of naltrexone 50 mg once daily for up to 12 weeks. Other 
dose regimens or durations of therapy were not evaluated in these trials” (Revia Package 
Insert 2013). 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 10 
 
Our starting dose and regimen are consistent with those recommended by the FDA for the 
treatment of alcoholism. 
 
2.3 Rationale 
 
 
While psychotherapy tailored specifically for PGD has proven effective in reducing PGD 
symptom severity in some people (Shear et al., 2005; Bryant et al., 2014),P 
Pthe acute and 
debilitating nature of the disorder highlights the need for pharmacological treatment that can 
act more rapidly, may help those for whom psychotherapy may not be effective, and/or may 
augment psychotherapy to promote PGD symptom grief resolution. Current evidence on 
pharmacological intervention for PGD is scarce. One barrier to testing pharmacologic agents 
has been the absence of PGD as a recognized mental disorder. Based on the clinical 
rationale that PGD exhibits similar symptoms to MDD and PTSD, selective serotonin 
reuptake inhibitors (SSRIs) have been explored in three open-label trials and one case 
series. While these studies demonstrate moderate effectiveness in reducing grief symptoms, 
the results are confounded by high rates of comorbid mental disorders, and the scientific 
rigor has been undermined by lack of randomization and blinding, small sample sizes and 
low levels of statistical power (Bui et al., 2012). The other medications trialed have include 
tricyclic antidepressants (TCAs) and benzodiazepines, both of which have not proven 
effective for the reduction of symptoms of PGD (Zygmont et al.,1998; Reynolds et al,. 1999). 
 
We believe that treating PGD as a disorder akin to MDD or PTSD is misguided, for two main 
reasons. The first reason is that PGD has been shown to demonstrate a distinct neural 
profile when compared to MDD or PTSD (Bryant et al., 2020). In contrast to conceptualizing 
PGD as a mood disorder such as MDD or a stress response syndrome such as PTSD, there 
is emerging evidence to suggest that PGD may be conceptualized as a reward dysfunction 
disorder, with the deceased proving the rewarding stimulus that the bereaved person craves 
(Kakarala et al., 2020). PGD, as noted above, is at its core a disorder of attachment and a 
craving and yearning for the deceased from whom they are separated (resulting in 
significant separation distress). In PGD, the primary gateway symptom required for 
diagnosis is yearning: persistent longing, pining for, or preoccupation with, the decreased. In 
this way, patients with PGD continue to “crave” their loved ones, even after they have died, 
due to the positive reinforcement provided by their memories of loved ones. The absence of 
the deceased creates a feeling of withdrawal – missing the person, feeling focused on his or 
her absence, feeling like life is not pleasurable and actually painful without the deceased, 
sorrow, resentment and agitation at being denied the support and security, meaning and 
identity the deceased provided.  
 
A second reason for treating PGD differently is that SSRIs take weeks to months to achieve 
full efficacy, when those suffering from PGD would benefit from faster acting interventions, 
especially given significant suicide attempt risk of those meeting criteria for PGD. 
 
Neurobiologically, numerous studies suggest that there are associations between symptoms 
of PGD and the reward pathway, which is the same pathway primarily responsible for 
addiction (Kakarala et al., 2020).P 
PThe reward pathway refers to a group of interconnected 
structures in the brain that uses dopamine as a signal to modulate the experience of reward. 
Some pertinent examples of enhanced activation in brain structures in PGD that are also 
important to the reward pathway include the nucleus accumbens (O’Connor et al., 2008) and 
orbitofrontal cortex (Bryant et al., 2020). 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 11 
 
Based on evidence supporting an association between PGD and neurobiological correlates 
of reward and addiction, we hypothesize that treatments for addiction might prove 
successful where those of MDD and PTSD have failed. Currently, disorders of addiction are 
treated with a wide variety of medications based upon the substance being abused, 
including: bupropion and varenicline for tobacco use; naltrexone and acamprosate for 
alcohol use; methadone and buprenorphine for opioid use (Klein 2016). Of these, we believe 
that naltrexone is the best medication to treat PGD when considering its mechanism of 
action, effects on social attachment, and side-effect profile. 
 
 
Mechanistically, naltrexone is a competitive antagonist of opioid receptors. These receptors, 
when bound by endogenous opioids released in response to rewarding stimuli, normally 
cause the subsequent release of dopamine in the reward pathway. Therefore, naltrexone 
may be an appropriate choice to treat PGD, as its mechanism of action directly impacts the 
reward pathway; by blocking opioid receptors, release of dopamine in the reward pathway is 
inhibited. It also has two practical advantages for patients. First, it can be administered orally 
(daily) or intramuscularly (monthly). Second, cost of oral naltrexone is affordable, ranging 
from $25 to $60 per month, often covered by insurance (Stahl 2014). 
 
Symptomatically, naltrexone targets two crucial aspects of PGD. First, assuming that having 
and maintaining social connections is vital to human functioning, the opioid theory of social 
attachment suggests that endogenous opioids are released during these experiences of 
social bonding, which then underlie the pleasant feelings of social bonding to positively 
reinforce the formation of such bonds. Based on this theory, studies have shown that 
naltrexone reduces feelings of social connection, especially to those closest to us (Inagaki et 
al., 2016; Inagaki et al., 2020).P 
PReduced positive associations with significant others, 
especially the deceased, may make bereavement feel less lonely and isolated while 
diminishing the reward derived from reminiscing about the deceased. Second, meta-analysis 
confirms that naltrexone reduces craving in patients with alcohol dependence; in PGD, 
craving the deceased is the core symptom (Hendershot et al., 2017; Prigerson et al. 2009). 
Thus, naltrexone may reduce the craving for the deceased, and thereby severity of PGD. 
Given these findings, we predict that naltrexone will provide a pharmacological way to 
dampen the benefits of social bonding while reducing the yearning for or craving for the 
deceased loved one, which would reduce the severity of PGD. 
 
The proposed study addresses both a conceptual and practical need regarding the 
treatment of PGD. Conceptually, the development of treatment for PGD is in its early stages, 
and studies concerning pharmacological treatment are especially lacking. Practically, 
patients with PGD are in dire need for a rapid, convenient, and effective intervention to 
promote their bereavement adjustment while diminishing the substantial risks posed by PGD 
for their mental and physical health and well-being. 
 
2.4  Risk/Benefit Assessment  
 
 
2.4.1 Known Potential Risks 
 
“After opioid detoxification, patients are likely to have reduced tolerance to opioids. As 
the blockade of exogenous opioids provided by naltrexone wanes and eventually 
dissipates completely, patients who have been treated with naltrexone may respond to 
lower doses of opioids than previously used, just as they would shortly after completing 
detoxification. This could result in potentially life-threatening opioid intoxication 


Protocol # 20-04021873 
6/18/21 
 
Page # 12 
 
(respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously 
tolerated doses of opioids…There is also the possibility that a patient who is treated with 
naltrexone could overcome the opioid blockade effect of naltrexone...This poses a 
potential risk to individuals who attempt, on their own, to overcome the blockade by 
administering large amounts of exogenous opioids. Any attempt by a patient to 
overcome the antagonism by taking opioids is especially dangerous and may lead to life-
threatening opioid intoxication or fatal overdose. 
 
The symptoms of spontaneous opioid withdrawal (which are associated with the 
discontinuation of opioid in a dependent individual) are uncomfortable, but they are not 
generally believed to be severe or necessitate hospitalization. However, when 
withdrawal is precipitated abruptly by the administration of an opioid antagonist to an 
opioid-dependent patient, the resulting withdrawal syndrome can be severe enough to 
require hospitalization. Symptoms of withdrawal have usually appeared within five 
minutes of ingestion of naltrexone and have lasted for up to 48 hours. 
 
 
 
Cases of hepatitis and clinically significant liver dysfunction were observed in association 
with naltrexone exposure during the clinical development program and in the 
postmarketing period. Transient, asymptomatic hepatic transaminase elevations were 
also observed in the clinical trials and postmarketing period. When patients presented 
with elevated transaminases, there were often other potential causative or contributory 
etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C 
infection, and concomitant usage of other potentially hepatotoxic drugs. 
 
Depression, suicide, attempted suicide and suicidal ideation have been reported in the 
postmarketing experience with naltrexone hydrochloride used in the treatment of opioid 
dependence. No causal relationship has been demonstrated. 
 
Naltrexone has been shown to increase the incidence of early fetal loss when given to 
rats at doses ≥ 30 mg/kg/day (180 mg/m2/day; 5 times the recommended therapeutic 
dose, based on body surface area) and to rabbits at oral doses ≥ 60 mg/kg/day (720 
mg/m2/day; 18 times the recommended therapeutic dose, based on body surface 
area)… Naltrexone should be used during pregnancy only if the potential benefit justifies 
the potential risk to the fetus” (Revia Package Insert 2013). 
 
2.4.2 Known Potential Benefits  
 
“Naltrexone is indicated in the treatment of alcohol dependence and for the blockade of 
the effects of exogenously administered opioids. The mechanism of action of Naltrexone 
in alcoholism is not understood; however, involvement of the endogenous opioid system 
is suggested by preclinical data” (Revia Package Insert 2013). 
 
2.4.3 Assessment of Potential Risks and Benefits 
 
The 7-10% of bereaving people estimated to be meet criteria for PGD have been shown 
to be at increased risk of medical conditions and diseases (e.g. hypertension, 
immunological dysfunction, cancer), substance abuse, physical and mental impairments, 
reduced quality of life, suicidal ideation and attempts, emergency room visits as well as 
multiple nights spent in the hospital (Trevino et al., 2018; Lannen et al., 2008; Prigerson 
et al., 1997; Holland et al., 2016; Zuckoff et al., 2006). The severe and substantial risks 


Protocol # 20-04021873 
6/18/21 
 
Page # 13 
 
posed by a PGD diagnosis highlight the need to investigate ways to help those suffering 
from this new mental disorder, such as pharmacologically with naltrexone. 
 
With respect to side-effects, naltrexone is well-tolerated. The most common side-effects 
of naltrexone include nausea, vomiting, abdominal pain, headache, and fatigue. To 
monitor these side-effects, we will ask participants to report any side-effects they may 
experience during their monthly visits. In addition, they will be provided a phone number 
to report side-effects at any time during the study. The most severe side-effect 
warranting an FDA black-box warning is hepatotoxicity that is based on studies in which 
the dose of naltrexone was far greater than recommended (300 mg vs 50 mg). 
Furthermore, in the COMBINE study, elevations in liver function tests (LFT) were seen in 
only 11 of 614 participants taking naltrexone, with most normalizing after cessation and 
no serious long-term consequences (Anton 2008). Accordingly, participants will be 
monitored monthly via blood tests to assess LFTs. In addition, although naltrexone can 
cause sudden and severe withdrawal in opiate users, we would not trial naltrexone in 
bereaved individuals who are opiate users. Similarly, participants who exhibit suicidal 
thoughts/behaviors or are pregnant will be screened out. 
 
The acute and debilitating nature of the disorder, in addition to the evidence 
demonstrating the increased risk of comorbities, highlights the need for pharmacological 
treatment that can act more rapidly, may help those for whom psychotherapy may not be 
effective, and/or may augment psychotherapy to promote PGD symptom grief resolution. 
A recent meta-analysis has found that naltrexone does not appear to increase the risk of 
serious adverse events over placebo (Bolton et al., 2019). When compared to the 
relative tolerability of naltrexone, it is clear that the use of this medication may yield 
tremendous benefits for patients with PGD not only to help them cope with the passing 
of a loved one, but as a preventative measure for more debilitating health issues that 
may arise from not treating this disorder.  
 
2.5 Correlative Studies Background 
 
 
Not applicable. 
 
3. Study Design 
 
3.1 Overall Design 
 
This is a randomized, placebo-controlled, triple-blinded (to healthcare professionals, 
participants, and data analysts), stage IV, single-site, pilot drug trial to establish the efficacy 
of using oral naltrexone as a pharmacological treatment for PGD. Specifically, we 
hypothesize that participants receiving naltrexone will demonstrate reduced PGD symptoms 
(via lower PG-13-R scores) when compared to placebo. We propose to enroll 48 participants 
at NYP-WCM who meet criteria for PGD. Participants will be randomly assigned to the 
naltrexone 50 mg oral arm or placebo arm; medications will be over-encapsulated to appear 
identical. Participants will take their assigned medication for 8 weeks, with monthly visits 
assess symptom severity, social closeness, and adverse reactions. Weekly surveys of PG-
13-R will be sent out to capture the temporal relationship between naltrexone use and PGD 
symptom severity. Follow-up 4 weeks after their last visit will assess the longevity of 
treatment, as well as any lingering adverse reactions. 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 14 
 
3.2 Scientific Rationale for Study Design 
 
Placebo was chosen as control in this study, for two reasons: (1) the presence of a placebo 
mitigates the placebo effect, and (2) there is a lack of treatment for PGD, meaning that most 
patients in real life are, by default, not receiving treatment at all (Shear et al., 2005). We 
propose the study design to be an RCT, because it allows us to make the trial to be one of 
superiority, minimizes biases, and minimizes confounding factors.  
 
Individuals with PGD who are not treated have been shown to be at increased risk of 
medical conditions and diseases (e.g. hypertension, immunological dysfunction, cancer), 
physical and mental impairments, reduced quality of life, suicidal ideation and attempts, 
emergency room visits as well as multiple nights spent in the hospital. 
 
3.3 Justification for Dose  
 
The use of naltrexone 50 mg PO daily is consistent with that which is recommended by the 
FDA to treat alcoholism. Duration of 8 weeks was chosen based on our expectation that 
naltrexone’s effects will be acute in nature, based on previous studies of naltrexone in 
alcoholism (Hendershot et al., 2017; Chick et al., 2000). Therefore, 8 weeks should be 
sufficient in duration to capture the effects of naltrexone. 
 
3.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she has completed all 
phases of the study including the last follow up-phase as shown in the Schedule of 
Assessments (SoA), Section 6.1. 
 
4. Subject Selection 
 
4.1 Study Population 
 
Subjects with a diagnosis of PGD who meet the inclusion and exclusion criteria will be 
eligible for participation in this study.   
 
4.2 Inclusion Criteria 
 
1. 18 years of age or older and younger than 90 years of age. 
2. Lives within a reasonable distance from NYPH for convenient clinic visits. 
3. Can speak, read, and write English proficiently. 
4. Meet diagnostic criteria for PGD based on/consistent with the DSM criteria (American 
Psychiatric Association, n.d.), which includes: 
a. Death of a person the bereaved survivor considered a significant other. 
b. Since the death, there has been a grief response characterized by intense 
yearning/longing for the deceased person or a preoccupation with thoughts or 
memories of the deceased person present nearly every day for the last month. 
c. As a result of the death, at least 3 of the following symptoms have been 
experienced nearly every day, for at least the last month: identity disruption (e.g. 
feeling as though part of oneself has died); marked sense of disbelief about the 
death; avoidance of reminders that the person is dead; intense emotional pain 
(e.g., anger, bitterness, sorrow) related to the death; difficulty moving on with life 


Protocol # 20-04021873 
6/18/21 
 
Page # 15 
 
(e.g., problems engaging with friends, pursuing interests, planning for the future); 
emotional numbness; feeling that life is meaningless; intense loneliness (i.e., 
feeling alone or detached from others). 
5. If a female patient, must agree to use a method of contraception and be willing and able 
to continue contraception during the first 8 weeks of the study while she is taking the 
study drug. Female patients who are planning to use oral hormonal contraception during 
this time must have initiated it at least 2 months prior to the baseline visit. 
6. If a male patient, must agree to use a method of contraception and be willing and able to 
continue contraception during the first 8 weeks of the study while he is taking the study 
drug. 
 
4.3 Exclusion Criteria  
 
 
 
1. Having recently started taking/prescribed medications for any psychiatric illness (e.g. 
SSRIs for MDD) within the past 3 months; participants who have been taking this 
medication for longer than 3 months can be included. 
2. Having recently started psychotherapy for any psychiatric illness within the past 3 
months; participants who have been receiving psychotherapy for longer than 3 months 
can be included. 
3. Prior history of recently active (e.g. within the past 3 months) opioid dependence. 
4. Current prescription, non-prescription, or illicit opioid use, (i.e., acute use within the past 
14 days or chronic use within the last 30 days), including opioid antagonists for alcohol 
or opioid dependence, all opioid analgesics, certain cough and cold remedies (e.g., 
codeine), and certain anti-diarrheal preparations (e.g., loperamide). 
5. Possible future use of opioids during the study (e.g. for surgery). 
6. Current use of leflunomide (Arava), droperidol (Droleptan), diazepam (Valium), 
thioridazine (Mellaril, Novoridazine, Thioril), or any other clinically relevant medication 
that has potential to cause liver injury with concurrent use of naltrexone. 
7. Currently pregnant, lactating, or planning to become pregnant during the study. 
8. Active hepatitis or liver disease. 
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels more than 
one standard deviation (SD) above the upper limit of normal on initial laboratory 
examination. 
10. Screen positive for active suicidal thoughts or behaviors. 
 
4.4 Lifestyle Considerations 
 
 
Not applicable. 
 
4.5 Screen Failures  
 
Screen failures are defined as participants who consent to participate in the clinical trial but 
are not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 16 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened later. Participants may be rescreened, if, during the duration of the enrollment 
period, the following reasons for screen failure changes: having started a medication for 
psychiatric illness within the past 3 months; having started psychotherapy for psychiatric 
illness within the past 3 months; cessation of leflunomide, droperidol, diazepam, thioridazine 
or other clinically relevant medication; no longer planning to be involved a future situation 
that may require opioids (e.g. surgeries); no longer planning to be pregnant; no longer 
endorsing suicidal thoughts or behaviors. Rescreened participants should be assigned the 
same participant number as for the initial screening. 
 
4.6 Strategies for Recruitment and Retention 
 
 
We predict an accrual rate of 60%, and therefore to meet the goal of enrolling NRtotal
R = 48, we 
anticipate a total screening of about 80 individuals. Recruitment methods include EPIC chart 
review, referrals, flyers, in-person recruitment, recruitment letters/emails, and posting online 
(e.g. ResearchMatch). Recruitment sources include the Cornell Center for Research on End 
of Life Care website, the department of Geriatrics and Palliative Medicine, the Department of 
Psychiatry, the Emergency Room, Medical Intensive Care Unit (MICU), local outpatient 
clinics (e.g. oncology, psychiatry), and local private practices (e.g. psychiatry).  
 
Once IRB-approval is obtained, we will list the study as open online, such as on the Cornell 
Center for Research on End-of-Life Care website and on ResearchMatch. We also will post 
study recruitment fliers with bereavement support groups and relevant clinics at WCM-
NYPH (e.g., the Wright Center for Aging, the Department of Geriatrics and Palliative 
Medicine bulletin-board; the Department of Psychiatry bulletin-board, cancer clinic bulletin-
boards; Acute Care for Elderly [ACE] unit). In addition, eligible individuals based on the 
inclusion criteria may be identified physicians and/or staff of these departments, who will 
then refer them to our study; individuals may be given an “Agree to Contact” form to 
complete at this time to allow study staff to contact the participant first. Similarly, co-
investigators may approach potential participants in WCM/NYP offices, and ask if they would 
be interested in the study. Trained co-investigators may either screen the participants at 
recruitment sites and/or ask for their contact information to be followed up at a time 
convenient for the potential participant. Participants may also be sent a recruitment 
letter/email after being identified via EPIC review for eligibility. NYP-WCM physicians may 
also identify potential participant patients for EPIC review. Apart from sources within the 
WCMC-NYP network, we will also contact outpatient psychiatry clinics and private 
psychiatry practices to make them aware of the study and refer patients. 
 
Participants will be compensated $25 after each visit for a total of $100 via ClinCard. 
 
All potential participants will be logged in a password-protected Excel file stored on a 
secured, shared server, which will contain their contact information, date of contact, 
eligibility, recruitment source, and dated of scheduled visit; identifiable health information will 
NOT be stored during recruitment. 
 
5. Registration Procedures 
 
5.1 Subject Registration (WCM only) 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 17 
 
Subjects will be registered within the WRG-CT as per the standard operating procedure for 
Subject Registration.  
 
 
 
5.2 Subject Registration (Sub-sites) 
 
      Not applicable. 
 
6. Study Procedures 
 
6.1 Schedule of Assessments 
  
Table 1. Schedule of trial events 
 
 
Pre-
Study 
Week 
1 
Week 
2 
Week 
3  
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9-11 
Week 
12 
Phone Screen 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
ICF 
 
X 
 
 
 
 
 
 
 
 
 
C-SSRS 
 
X 
 
 
X 
 
 
 
X 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
Sociodemographics  
X 
 
 
 
 
 
 
 
 
 
Review of 
Medications 
 
X 
 
 
X 
 
 
 
X 
 
 
SCIP 
 
X 
 
 
X 
 
 
 
X 
 
X 
IOS Scale 
 
X 
 
 
X 
 
 
 
X 
 
X 
SIQ 
 
X 
 
 
X 
 
 
 
X 
 
X 
ISEL 
 
X 
 
 
X 
 
 
 
X 
 
X 
SCS 
 
X 
 
 
X 
 
 
 
X 
 
X 
Health Behaviors 
Survey 
 
X 
 
 
X 
 
 
 
X 
 
X 
Blood Sample 
 
X 
 
 
X 
 
 
 
X 
 
 
Urine Pregnancy 
Test 
 
X 
 
 
X 
 
 
 
X 
 
 
Tablet Counting 
 
 
 
 
X 
 
 
 
X 
 
 
Study Drug 
Dispensation 
 
X 
 
 
 
 
 
 
 
 
 
Review of Side 
Effects 
 
 
 
 
X 
 
 
 
X 
 
X 
PG-13-R 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
6.1.1 Phone Screen 
 
Interested potential participants will contact study staff via telephone. This phone call will 
be used to screen participants. Study staff will briefly explain the study and confirm 
participant interest. Study staff will then read the inclusion and exclusion criteria to the 
participant; no identifiable health information will be recorded at this time. If the 


Protocol # 20-04021873 
6/18/21 
 
Page # 18 
 
participant confirms that they are eligible with the criteria, they will be scheduled for an 
initial clinic visit, preferably within the week of calling  
 
 
 
 
6.1.2 Treatment Phase  
 
Eligible subjects will be randomly assigned to naltrexone or placebo treatment groups in 
a 1:1 ratio using a computer-generated randomization scheme developed by the data 
manager.   
 
Participants will be sent weekly PG-13-R surveys through email via REDcap. 
Alternatively, if requested, participants can fill this survey out over the phone. 
 
 
6.1.2.1 Visit 1 (baseline; Day 0) 
 
SCIP 
 
C-SSRS 
 
Medical History 
 
ICF 
 
Sociodemographics 
 
Review of Medications 
 
IOS Scale 
 
Social Integration Questionnaire 
 
Interpersonal Support Evaluation List 
 
Social Connectedness Survey 
 
Health Behaviors Survey 
 
Blood sample (LFTs) 
 
Urine Pregnancy Test 
 
Dispense medication (8-week supply of 56 tablets) 
 
6.1.2.2 Visit 2 (+28 days) 
 
SCIP 
 
C-SSRS 
 
Review of medications 
 
Review of side-effects 
 
IOS Scale 
 
Social Integration Questionnaire 
 
Interpersonal Support Evaluation List 
 
Social Connectedness Survey 
 
Health Behaviors Survey 
 
Blood sample (LFTs) 
 
Urine Pregnancy Test 
 
Tablet counting 
 
 
     6.1.2.3 Visit 3 (+28 days) 
 
SCIP 


Protocol # 20-04021873 
6/18/21 
 
Page # 19 
 
 
C-SSRS 
 
Review of medications 
 
Review of side-effects 
 
IOS Scale 
 
Social Integration Questionnaire 
 
Interpersonal Support Evaluation List 
 
Social Connectedness Survey 
 
Health Behaviors Survey 
 
Blood sample (LFTs) 
 
Urine Pregnancy Test 
 
Tablet counting/Return medication 
6.1.3 Follow-up Phase (+28 days) – administered via REDcap  
o Review of side-effects 
o PG-13-R 
o IOS scale 
o Social Integration Questionnaire 
o Interpersonal Support Evaluation List 
o Social Connectedness Survey 
o Health Behaviors Survey 
7. Study Intervention 
 
7.1 Study Intervention/Device Description   
 
Naltrexone HCl 50 mg is an oral medication in tablet form purchased from an FDA licensed 
drug wholesaler. Naltrexone will be compounded and packed into a gelatin capsule stable 
for 6 months at room temperature with instruction to be taken as is PO with a glass of water. 
Placebo will be composed of a filler material (e.g. lactose or methyl cellulose) will be 
identical in appearance to naltrexone via over-encapsulation. 
 
7.2 Availability 
 
Oral naltrexone and placebo will be supplied by Doyle’s Pharmacy, located at 2425 Sunset 
Blvd, Houston, TX 77005. 
 
7.3 Acquisition and Accountability  
 
 
 
Naltrexone and all other supplies needed (gelatin capsules, filler material, etc.) will be 
ordered by George Handal, Compounding Pharmacist at Doyle’s Pharmacy. Order for all 
items will be filled and delivered to Doyle’s within 30 days from order date. 
 
 
Phone: 713-526-1771      Fax: 713-526-1775        Cell: 832-541-9048.                 
 
UAgent Inventory Records/Device LogsU – The investigator, or a responsible party designated 
by the investigator, will maintain a careful record of the inventory and disposition of all 


Protocol # 20-04021873 
6/18/21 
 
Page # 20 
 
agents/device received from Doyle’s Pharmacy on a Drug Accountability Record Form 
(DARF) or Device Log.  
 
7.4 Formulation, Appearance, Packaging, and Labeling  
 
Naltrexone HCl 50 mg is a beige, round, biconvex, film-coated, scored tablet. These tablets 
will be over-encapsulated by a gelatin capsule. A placebo composed of filler material (e.g. 
lactose of methyl cellulose) encapsulated by the same gelatin capsule will be identical in 
appearance to naltrexone. The tablets are packaged into 60-cc white, high-density 
polyethylene (HDPE) bottles fitted with child-resistant closures with foil induction seals, each 
containing 56 tablets. Each bottle also contains a polyester coil as bottle filler.  
 
 
The supplies will be labeled in accordance with all applicable guidelines and/or 
regulations. Bottles will be labeled as such that only pharmacists of Doyle’s Pharmacy will 
know which ones contain naltrexone and which ones contain placebo; this information will 
only be shared with the PI. 
 
The manufacture of both naltrexone and placebo will be overseen by George Handal, 
director of compounding for Clinical Trials at Doyle’s Pharmacy. 
 
 
7.5 Product Storage and Stability 
 
 
Store at 20° to 25°C (68° to 77°F) in the provided container. 
 
7.6 Preparation 
 
A Master Formula Record is prepared based on USP 795 approved methods along with 
needs and requirements of study staff and participants detailing how we plan to proceed. 
 
A Compounding Record is prepared as the product is being compounded including product 
name, quantity, manufacturer, lot #, Exp. Date of all supplies used. Both records are 
inspected, verified, signed and dated by 2 pharmacists that participated in the compounding. 
 
Naltrexone and placebo will be packaged separately in bottles of quantities of 56 and 
labeled appropriately so that the pharmacy can keep track of which is which. There is no 
preparation needed to be done by the study staff or participants. 
 
7.7 Dosing and Administration 
 
All participants will take their assigned medication daily for 8 weeks, starting the day after 
their first visits. This medication will be dispensed once during visit 1. For naltrexone, the 
dose will be 50 mg. Participants will be advised to take it around lunchtime, but this is not a 
strict requirement; naltrexone can be taken with or without food. There is no anticipated 
adverse reaction from stopping naltrexone at any point in the study, therefore there is no 
maximum or minimum duration.  
 
If participants miss a dose, they can resume the normal schedule the next day; there is no 
need to compensate for any missed doses. 


Protocol # 20-04021873 
6/18/21 
 
Page # 21 
 
 
7.7.1 Dosing Delays/Dose Modifications 
 
 
      Not applicable. 
 
7.8 General Concomitant Medication and Supportive Care Guidelines 
 
“Studies to evaluate possible interactions between naltrexone and drugs other than opiates 
have not been performed…Patients taking naltrexone may not benefit from opioid containing 
medicines, such as cough and cold preparations, antidiarrheal preparations, and opioid 
analgesics. In an emergency situation when opioid analgesia must be administered to a 
patient receiving naltrexone, the amount of opioid required may be greater than usual, and 
the resulting respiratory depression may be deeper and more prolonged” (Revia Package 
Insert 2013).  
 
Given that other psychiatric medications may have an effect on PGD symptom severity, 
concomitant use will only be allowed if the participant has been using that medication 
consistently for the past 3 months prior to the start of the study; otherwise, participants who 
do not meet this criteria will be screened out. 
 
Concomitant use of medications known to cause liver damage, as outlined in the exclusion 
criteria (section 4.3), are not allowed to be used during the study due to concern of 
potentiated liver injury with concurrent use of naltrexone. 
 
All concomitant medications will be recorded and/or updated on subject medication log 
throughout the course of the study and saved in subject binder, if applicable. 
 
7.9 Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 8 
weeks or until one of the following criteria applies: 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Subject decides to withdraw from the study, or 
• 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
  
7.10 Duration of Follow Up 
 
Subjects will be followed for 1 week after removal from study. Subjects removed from study 
for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
 
 
7.11 Measures to Minimize Bias: Randomization and Blinding  
 
The pilot RCT is a single site, triple-blind, block-randomized study designed primarily to 
establish the feasibility of conducting a larger, definitive trial of the intervention and to explore 
the intervention’s potential efficacy. It will be of 1:1 parallel group design to compare the 


Protocol # 20-04021873 
6/18/21 
 
Page # 22 
 
efficacy of naltrexone treatment in alleviating grief intensity, as measured in PG-13-R, 
against placebo-control group among bereaved population meeting diagnostic criteria for 
prolonged grief disorder. 
 
The research statistician will use R software to generate a random sequential list of binary 
codes by participant number. Blocks of fixed length will be applied to keep the number of 
both arms relatively balanced. Set seed function will be used to ensure that the 
randomization schedule is reproducible. Participants having consented and passing the 
inclusion criteria will enter the randomization section and be assigned with the appropriate 
number and corresponding intervention upon confirmation. 
 
Trial randomization codes will be kept on a password-protected Excel sheet located on a 
secure server. Notably, this Excel sheet itself will not contain any information pertaining to 
which codes correspond to which arm of treatment to maintain blinding; only the PI and 
Doyle’s pharmacy will have this information.  
 
Because this is a triple-blinded study, all the participants, research staffs, healthcare 
providers and statisticians will be blinded to the type of intervention the participant received. 
This level of blinding is maintained throughout the conduct of the trial, and only when the 
data are analyzed according to statistical analysis plan, and conclusions regarding the 
primary and secondary outcomes are made, will the associated personnel be unblinded. 
  
The Principal Investigator (PI) at a site may break the blind in the event of an immediate 
medical emergency (e.g. SAE) or abnormal serum laboratory results (e.g. elevation in LFTs), 
where knowledge of the study participant’s treatment assignment must be known in order to 
facilitate appropriate medical treatment. In these situations, the Investigator must first 
attempt to contact the study medical monitor before unblinding a participant’s treatment 
identity in order to obtain concurrence that unblinding a study participant’s treatment 
assignment is necessary. The one exception to obtaining concurrence with the medical 
monitor is in the event that a participant tests positive for pregnancy; if this occurs, the PI can 
and should immediately break the blind in order to follow the procedure laid out in section 
13.1.7. If a study participant’s treatment identity is unblinded by the study site, the unblinding 
must be documented on the CRF. 
  
The PI is responsible for ensuring that the instructions on how to perform a code break are 
stored safely, that their location is known, and that access is readily available to the relevant 
staff in case of an emergency. 
 
In regards to the treatment, Naltrexone HCl will be over-encapsulated with a gelatin capsule 
so as to be identical in appearance to placebo. Furthermore, both naltrexone and placebo 
will be packaged in identical bottles.  
  
Given that naltrexone can cause elevations in LFTs, this may be a cause of imperfect 
blinding. However, we believe this risk is mitigated by three factors. First, based on the data 
from the COMBINE study showing that only 2% of participants experienced elevated LFTs, 
statistically it is unlikely that more than 1 participants will also experience this adverse effect 
in one arm (probability of even is <1.2%). Second, in cases of significant elevation in LFTs, 
unblinding will have to occur regardless to address this medical emergency. Third, one 
designated member of the study staff will review laboratory results and will be shielded from 
other members of the study staff. Any concerning and significant elevation will be reported to 


Protocol # 20-04021873 
6/18/21 
 
Page # 23 
 
the PI, who remains unblinded throughout the duration of the entire study. Furthermore, 
study staff analyzing data will not have access to these data until all other statistical analyses 
have been performed, where it will be used to the incidence rate.  
 
7.12 Study Intervention/Follow-up Compliance 
 
Adherence to protocol involves attending all visits and taking at least 80% of their 
medication. Three consecutive daily attempts during the week of the scheduled visit will be 
made to reschedule a participant’s visit. Medication compliance will be evaluated by 
counting returned tablets; participants will be asked to bring their bottle of medication at 
every visit. Participants will also be asked if there was any difficulty in taking the medication 
during each visit. Adherence will be tracked in a drug accountability log/Excel file. Failure to 
meet either of these standards will result in that participant being considered “lost to follow-
up”. 
 
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
8.1 Discontinuation of Study Intervention 
 
Criteria for discontinuing the study intervention are outlined in section 8.2. If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse 
event (AE). Discontinuation of the intervention will be permanent; participants who 
discontinue the study intervention will not be allowed to restart the intervention at a later 
date.  
 
Participants who discontinue the study intervention before their 2Pnd
P visit will be scheduled for 
a visit within 7 days of discontinuation to undergo the same procedures of the 3Prd
P visit as 
outlined in section 6.1.2.3, and then skip to the follow-up phase 28 days after the hastened 
visit. Participants who discontinue the study intervention after their 2Pnd
P visit but before their 
3Prd
P visit will likewise be scheduled for a visit within 7 days of administration to undergo the 
same procedures of the 3Prd
P visit as outline in section 6.1.2.3, and then proceed to the follow-
up phase. 
 
In addition to the data collected at 3Prd
P visit as outlined in section 6.1.2.3, data to be collected 
at the time of study intervention discontinuation will include why the study intervention was 
discontinued.   
 
8.2 Participant Discontinuation/Withdrawal from the Study 
 
Participants are free to withdraw from participation in the study at any time and for any 
reason upon request without penalty or loss of benefits to which the study participant is 
otherwise entitled. 
 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance. 


Protocol # 20-04021873 
6/18/21 
 
Page # 24 
 
• 
If any clinical adverse event (AE), laboratory abnormality (e.g. elevated LFTs), or 
other medical condition or situation occurs such that continued participation in the 
study would not be in the best interest of the participant. 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
• 
Participant loses medication. 
• 
Participant lost to follow-up after 3 attempts to contact subject to schedule study visit. 
The reason for participant discontinuation or withdrawal from the study will be recorded on 
the CRF. Subjects who sign the informed consent form and are randomized but do not 
receive the study intervention may be replaced. Subjects who sign the informed consent 
form, and are randomized and receive the study intervention, and subsequently withdraw, or 
are withdrawn or discontinued from the study, will not be replaced. 
8.3 Lost to Follow Up 
 
A participant will be considered lost to follow-up if he or she fails to return for any scheduled 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 
the week of their scheduled visit and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
9. Correlative/Special Studies  
 
Not applicable 
 
10. Measurement of Effect 
 
10.1 Response Criteria 
 
 
 Prolonged grief symptom severity will be evaluated by the PG-13-R scale; a decrease in 
symptom severity would be reflected by a lower score on the scale. More details about the 
PG-13-R scale can be found in section 1.2.4. 
 
10.2 Duration of Response  
 
 
Not applicable. 


Protocol # 20-04021873 
6/18/21 
 
Page # 25 
 
 
10.3 Progression-Free Survival  
 
 
Not applicable. 
. 
10.4 Other Response Parameters 
 
 
 
 
Other endpoints used in the study are found in section 1.2.5. 
 
11. Data Reporting / Regulatory Considerations 
 
11.1 Data Collection 
 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, 
efficacy, and adverse event data for all enrolled subjects.  
 
11.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for 
the creation of customized, secure data management systems that include Web-based 
data-entry forms, reporting tools, and a full array of security features including user and 
group based privileges, authentication using institution LDAP system, with a full audit 
trail of data manipulation and export procedures. REDCap is maintained on CTSC-
owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through a 
multi-institutional consortium led by the Vanderbilt University CTSA. 
 
11.2 Regulatory Considerations 
 
11.2.1 Institutional Review Board/Ethics Committee Approval  
 
As required by local regulations, the Investigator will ensure all legal aspects are covered, 
and approval of the appropriate regulatory bodies obtained, before study initiation.  
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the participants, and any other relevant study documentation will be 
submitted to the appropriate Ethics Committee. Written approval of the study and all 
relevant study information must be obtained before the study center can be initiated or the 
IP is released to the Investigator. Any necessary extensions or renewals of IRB approval 
must be obtained for changes to the study, such as amendments to the protocol, the ICF, 
or other study documentation. The written approval of the IRB together with the approved 
ICF must be filed in the study files.  
The Investigator will report promptly to the IRB any new information that may adversely 
affect the safety of the participants or the conduct of the study. The Investigator will submit 
written summaries of the study status to the IRB as required. On completion of the study, 
the IRB will be notified that the study has ended.  
 
All agreed protocol amendments will be clearly recorded on a protocol amendment form 
and will be signed and dated by the original protocol approving signatories. All protocol 


Protocol # 20-04021873 
6/18/21 
 
Page # 26 
 
amendments will be submitted to the relevant institutional IRB for approval before 
implementation, as required by local regulations. The only exception will be when the 
amendment is necessary to eliminate an immediate hazard to the trial participants. In this 
case, the necessary action will be taken first, with the relevant protocol amendment 
following shortly thereafter.  
Once protocol amendments or consent form modifications are implemented at the lead 
site, Weill Cornell Medicine, updated documents will be provided to participating sites, as 
applicable. Weill Cornell Medicine must approve all consent form changes prior to local 
IRB submission.  
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended.  
 
11.2.2 Ethical Conduct of the Study  
The Investigators and all parties involved should conduct this study in adherence to the 
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the 
applicable national and local laws and regulatory requirements.  
 
This study will be conducted under a protocol reviewed and approved by the applicable 
ethics committees and investigations will be undertaken by scientifically and medically 
qualified persons, where the benefits of the study are in proportion to the risks. 
 
11.2.3 Informed Consent 
 
The investigator or qualified designee must obtain documented consent according to ICH-
GCP and local regulations, as applicable, from each potential subject or each subject’s 
legally authorized representative prior to participating in the research study. Subjects who 
agree to participate will sign the approved informed consent form and will be provided a 
copy of the signed document.   
 
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements, 
applicable laws and regulations. 
 
11.2.4 Compliance with Trial Registration and Results Posting Requirements  
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to 2TUhttp://www.clinicaltrials.govU2T. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information. 
 
11.2.5 Record Retention 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 27 
 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced.  After completion of the study, all 
documents and data relating to the study will be kept in an orderly manner by the 
Investigator in a secure study file.  Essential documents should be retained for 2 years 
after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the IP. In addition, all subjects medical records 
and other source documentation will be kept for the maximum time permitted by the 
hospital, institution, or medical practice.   
 
12. Statistical Considerations 
 
12.1 Study Design/Endpoints 
 
The pilot RCT will be a single site, triple-blind, block-randomized study to test efficacy of 
Naltrexone treatment in alleviating grief intensity, as measured in PG-13-R, in comparison to 
placebo-control group among population with prolonged grief disorder. The allocation ratio 
will be 1:1. 
 
The primary outcome is participants’ changes in PG-13-R scores comparing 2-month follow-
up to baseline. PG-13-R is an 11-item measurement tool for Prolonged Grief Disorder (PGD) 
symptoms evaluation ranging from 11 to 55.  
 
Since it is a small-scale trial, it is unlikely that there is any meaningful discouraging or 
encouraging primary results prior to the end of the trial. Therefore, no interim analysis will be 
imposed for the trial as the goal of the study is gathering evidence for efficacy/futility at the 
end of the study. Instead, the trial might be halted if abnormally high adverse event rate is 
observed (>=3 events in any arm, p=0.012). 
 
12.2 Sample Size/Accrual Rate 
 
The pilot RCT is designed primarily to establish the feasibility of conducting a larger, 
definitive trial of the intervention and to explore the intervention’s potential efficacy. We, 
nonetheless, calculated power for the pilot RCT.  
 
According to previous studies tracing grief intensity changes across time among the 
bereaved sample (Prigerson et al., 2013; Boelen et al., 2010), we estimate a natural decline 
of 1.0 in PG-13-R scores during a period of 2 months with a standard deviation of 6.0, for 
patients of 12 to 18 months post bereavement. Meanwhile, we propose a 20% decline from 
baseline PG-13-R (6 in scores) for treatment group. The effect size (Cohen’s d) was then 
assumed to be 0.83. The null hypothesis is that comparing to placebo-controlled group, 
naltrexone treatment at 50 mg mitigates grief intensity among patients with prolonged grief 
disorder in a 2-month period. With 48 participants (n=24 naltrexone arm; n=24 placebo arm) 
and an interim analysis at 50% information fraction, we expect to have 80% power (Type II 
error<0.2) to detect a significant difference (Type I error <0.05) in PG-13-R baseline-to-2-
month scores comparing the intervention and control groups. The accrual rate is expected to 
be 6 participants per month with the recruitment period spanning over 9-12 months. 
 
12.3 Stratification Factors  
 


Protocol # 20-04021873 
6/18/21 
 
Page # 28 
 
No stratification factor is applicable to this single-site pilot study. 
 
 12.4 Analysis of Endpoints 
 
12.4.1 Analysis of Primary Endpoints 
 
PG-13-R baseline-to-2-month scores for each participant will be calculated as 
participants’ PG-13-R scores at 2-month follow-up minus the scores at baseline. Two 
sample t-test comparing the PG-13-R baseline-to-2-month scores between intervention 
and control groups will be conducted as primary statistical analysis. If the normality 
assumption for t-test is breached, Wilcoxon rank-sum test will be used instead. In 
addition, multivariate linear regression model will be fitted to adjust for confounders. All 
statistical tests will be two-sided. 
 
In addition to, PG-13-R baseline-to-1 month scores, PG-13-R baseline-to-3 month 
scores will be calculated separately. Two sample t-test comparing each type of scores 
between intervention and control groups will be conducted as secondary statistical 
analyses. If the normality assumption for t-test is breached, Wilcoxon rank-sum test will 
be used instead. In addition, multivariate linear regression model will be fitted to adjust 
for confounders. 
 
Simultaneously, two-sample proportion test will be conducted for SCIP diagnosis at 1 
month, 2 months and 3 months post baseline. If the approximation assumption for 
proportional test is breached, Fisher’s exact test will be used instead. In addition, 
multivariate logistic regression model will be fitted to adjust for confounders. All statistical 
tests will be two-sided. 
 
12.4.2 Analysis of Secondary Endpoints 
 
We will first examine bivariate associations (e.g., using Pearson correlation coefficients) 
between the score on the IOS (in which lower scores will reflect less “integration with 
other” as represented by the quantified degree of circle overlap) and assignment to 
naltrexone vs. placebo. We also expect IOS scores to be related to reductions in PG-13-
R scores and CSSRS scores of suicidal ideation and scores of greater social integration 
and support (SIQ and ISEL, respectively). Assuming that linear regression analyses 
indicate that naltrexone is significantly associated with reductions in PG-13-R scores and 
IOS scores, and that IOS scores are significantly associated with PG-13-R scores, we 
will then regress PG-13-R scores on naltrexone and IOS scores. If the effect of 
naltrexone loses statistical significance in relation to PG-13-R scores, then following 
Baron and Kenney’s method of testing for mediation, it can be concluded that IOS 
scores (i.e., social integration) is a mediator and the mechanism through which 
naltrexone operates to reduce PGD symptomatology. 
 
12.5 Interim Analysis 
 
Since this is a small-scale trial, it is unlikely that there is any meaningful discouraging or 
encouraging primary results prior to the end of the trial. Therefore, no interim analysis will be 
imposed for the trial as the goal of the study is gathering evidence for efficacy/futility at the 
end of the study. 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 29 
 
 12.6 Reporting and Exclusions 
 
12.6.1 Evaluation of Toxicity 
 
All subjects will be evaluable for toxicity from the time of their first treatment with 
naltrexone.  
 
12.6.2 Evaluation of Response 
 
All subjects included in the study will be assessed for response to treatment if they have 
received at least 4 weeks’ worth of naltrexone; we will conduct a secondary analysis to 
explore whether the treatment has an effect in a shorter time frame. 
 
13. Adverse Event Reporting Requirements  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation. Safety will be monitored by evaluation of adverse 
events reported by subjects at each monthly visit or by phone at any time, or observed by 
investigators or research staff, as well as by other investigations such as clinical laboratory 
tests. 
 
13.1 Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug and does not imply any judgment about causality. An 
adverse event can arise with any use of the drug (e.g., off-label use, use in combination with 
another drug) and with any route of administration, formulation, or dose, including an 
overdose.  
 
 
13.1.1 Investigational Agent (Expected Adverse Events) 
 
The most common side-effects of naltrexone include nausea, vomiting, abdominal pain, 
headache, and fatigue. The most severe side-effect is hepatotoxicity. Opioid withdrawal 
can be sudden and severe in participants who are dependent on opioids. 
 
13.1.2 Adverse Event Characteristics and Related Attributions 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site (2Thttp://ctep.cancer.gov2T). 
 
• 
Severity of the AE: 
o Mild (Grade 1) - asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Moderate (Grade 2) - minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL. 


Protocol # 20-04021873 
6/18/21 
 
Page # 30 
 
o Severe (Grade 3) - medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. 
o Life-threatening (Grade 4) - Life-threatening consequences; urgent 
intervention indicated. 
o Fatal (Grade 5) – Death related to AE 
• 
Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
13.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a subject specific AE log. The AE log will be 
maintained by the research staff and kept in the subject’s research chart.    
 
 
13.1.4 Reporting of AE to WCM IRB 
 
All AEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
2Thttp://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf2T.  
 
13.1.5 Reporting Events to Participants 
 
Participants will undergo blood testing at every monthly clinic visit. If a participant’s LFTs 
are found to be significantly elevated at any time, study staff will contact the participant 
via phone to inform them and terminate their participation in the study. At T2, T3, and 
T4, participants will be asked to report any new side effects that they may have 
experienced after starting the study. If these side effects are clinically suspected to be 
related to/caused by naltrexone, participants will be asked to terminate their participation 
in the study. Participants will also be able to contact the PI via the phone number listed 
on the ICF at any time to report adverse effects and may be asked to come into clinic for 
further evaluation and termination in the study if necessary. 
 
13.1.6 Events of Special Interest 
 
Not applicable. 
 
13.1.7 Reporting of Pregnancy 
 
Naltrexone is classified as a class C medication; a recent prospective cohort study of 
pregnant women taking naltrexone showed no adverse effects to the fetus (Towers et 
al., 2020). Nevertheless, participants who are pregnant will be screened out. Female 
participants must agree not to become pregnant and male participants must agree not to 
impregnate a female during the first 8 weeks of the study in which he/she will be taking 
the study drug; recommended methods of contraception are outlined in the consent 


Protocol # 20-04021873 
6/18/21 
 
Page # 31 
 
form. Participants who become pregnant during the first 8 weeks will be terminated from 
the study and will stop taking the assigned medication. Participants will then be followed 
for 1 week, and then asked for permission to follow to pregnancy outcome. 
 
Additionally, female partners of male subjects will not be followed. According to the FDA 
package insert, naltrexone had no effect on male fertility in rats who were given 16 times 
the recommended therapeutic dose. There is no further evidence to suggest paternal 
teratogenicity. 
 
13.2 Definition of SAE 
 
Serious adverse events (SAEs) include death, life threatening adverse experiences, 
hospitalization or prolongation of hospitalization, disability or incapacitation, 
overdose, congenital anomalies and any other serious events that may jeopardize 
the subject or require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
 
13.2.1 Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:   
2Thttps://research.weill.cornell.edu/sites/default/files/immediate_reporting_policy.pdf2T.  
 
13.2.2 Reporting of SAE to FDA  
 
Not applicable as this study does not require an IND. This study is exempt because: it is 
lawfully marketed in the United States; is not intended to be reported to FDA as a well-
controlled study in support of a new indication given that this is pilot study and there is 
no intent to use it to support any other significant change in the labeling of the drug or 
advertising for the drug; does not involve a route of administration, dose, patient 
population, or other factors that significantly increases the risk associated with use of the 
drug product given that we are administering the drug based on FDA recommendations 
(50 mg PO). 
  
13.2.3 Reporting of SAE to Doyle’s Pharmacy 
 
Institution will send Doyle’s Pharmacy copies of any and all serious adverse event 
reports filed with the FDA or other applicable regulatory authorities, as well as copies of 
any correspondence with the FDA or other applicable regulatory authorities, regarding 
any and all serious adverse events, irrespective of association with the Study Drug(s) in 
the course of the Clinical Trial, within 7 business days of such report or correspondence 
being sent to the FDA or other applicable regulatory authorities. Copies should be faxed 
directly to George Handal at 713-526-1775.  
 
 
13.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the subject 
discontinues participation from the study. Participants will be referred to an NYP internist for 


Protocol # 20-04021873 
6/18/21 
 
Page # 32 
 
follow-up. Research staff will then contact the participant 7 days after their appointment to 
confirm that AE/SAE has stabilized; if AE/SAE has not stabilized at this time, then study staff 
will continue to call the participant weekly until stabilization has occurred. 
 
13.4 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 through 
blood tests performed at each monthly visit, urine pregnancy tests performed at each visit, 
interviews of a study participant during each study visit at which he/she will be asked to 
report adverse effects, or upon review by a study monitor. Participants will also be able to 
contact the PI via the phone number listed on the ICF at any time to report adverse effects. 
All adverse effects will be unsolicited, given that the most severe side effect will be 
monitored objectively via laboratory testing.  
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate CRF. 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. Study staff will follow up with participants 
experiencing AEs 7 days after appearance of events via phone. If AEs are not resolved by 
then, study staff will continue to call weekly; 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.  
 
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. 
 
 
Study staff 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. 
 
14. Unanticipated Problems Involving Risks to Subjects or Others 
 
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSO) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 


Protocol # 20-04021873 
6/18/21 
 
Page # 33 
 
• 
Related or possibly related to participation in the research (“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); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
14.1.2 Unanticipated Problem Reporting 
 
The investigator will report unanticipated problems (UPIRTSOs) to the reviewing 
Institutional Review Board (IRB) and to the lead principal investigator (PI). The 
UPIRTSO 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 UPIRTSO;  
• 
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UPIRTSO. 
 
To satisfy the requirement for prompt reporting, UPIRTSOs will be reported using the 
following timeline:   
 
• 
UPIRTSOs that are serious adverse events (SAEs) will be reported to the IRB 
and to the PI within 3 days of the investigator becoming aware of the event.  
• 
Any other UPIRTSO will be reported to the IRB and to the PI within 7 days 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 the Office for Human Research Protections (OHRP) within 7 days 
of the IRB’s receipt of the report of the problem from the investigator. 
 
15. Data and Safety Monitoring Plan (DSMP) 
 
For safety, we propose using an independent medical monitor, as we believe that the risks posed 
to participants is low, given that naltrexone is well-tolerated. We nominate Dr. Janna S. Gordon-
Elliott to serve as our medical monitor. Dr. Gordon-Elliott is an Attending Psychiatrist and 
Assistant Clinical Professor of Psychiatry at New York-Presbyterian Hospital/Weill Cornell 
Medicine. At NYP/WCM, Dr. Gordon-Elliott, a Consultation-Liaison Psychiatrist, has been active 
in the care of medically-ill individuals with psychiatric and behavioral conditions. Her current 
clinical work focuses on mental health and resilience in young adults, including college and 
graduate medical students. In her faculty practice, she specializes in psychotherapy and 
psychopharmacology, with interests in women's health, depression and anxiety, sports 
psychiatry, and mental health in the setting of medical illness. She has served as our psychiatry 
consultant for many of the clinical trials of the Center for End-of-Life Research Center. 
 
Blood samples will be collected monthly to monitor elevations in LFTs, as hepatotoxicity is a 
known, but rare, severe adverse effect of naltrexone. Participants will also be asked to report any 
new side effects that they may have experienced after starting the study during visits. Participants 


Protocol # 20-04021873 
6/18/21 
 
Page # 34 
 
will also be able to contact the PI via the phone number listed on the ICF at any time to report 
adverse effects. All AEs and SAEs will be reviewed weekly to the independent medical monitor. 
The medical monitor’s comments/review will be submitted to the IRB at the time of continuing 
review and submitted to participating sites upon receipt of review comments. 
 
Adverse events that may cause the subject to terminate protocol treatment include an elevation 
of LFTs twice that of baseline, as well as any other adverse effects that significantly affects quality 
of life.  
 
Study stopping rules are based on efficacy and safety. In regard to efficacy, the study will be 
terminated if the t-test statistic at interim analysis is > 3.30. In regard to safety, the study will be 
suspended if >3 participants in either arm are found to have significantly elevated LFTs. The PI 
will review these adverse events, and if these events are occurring within the naltrexone arm, 
then the study will be terminated. If these events are found to be occurring within the placebo 
arm, then those participants affected will be suspended from the study until receiving clearance 
from a physician. 
 
Data gathered for this study will be obtained from interviews, questionnaires, assessments, and 
laboratory test results. Data collected from respondents will only be identified via a study ID that 
will serve as a link to identifiable information. Similarly, on CRFs or other documents submitted to 
outside parties, participants will be identified by no more than their participant identification 
number. All participant identifiable information will be kept in a password protected electronic 
database, REDCap. This information will also be kept in hard copy format in a locked file cabinet 
within a locked office and will only accessible to the study PI and relevant study staff.  
 
Confidentiality will be ensured by removal of identifying information (name, age, gender, 
race/ethnicity, length of service) of participants and substituting their name with a study participant 
number. As noted, all data will be de-identified. Nonetheless, we will maintain a file that links 
subject name with the study participant number thereby enabling us to locate the study 
participant’s research record upon request. Data will be analyzed in aggregate only, and no 
identities will be revealed. 
 
Data collected will be obtained by trained and experienced research staff interviewing study 
participants. The data will be used specifically for the purposes outlined in this proposal and not 
for any other purpose. All study related documents will be stored in a secure location until the 
study has ended and all data analyses are complete. At that time, all study material will be placed 
in a secured long-term storage facility until it is deemed appropriate to destroy the study material. 
 
 
 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 35 
 
16. References 
 
American Psychiatric Association. View and Comment on Recently Proposed Changes to 
DSM–5. (n.d.). Retrieved from 2Thttps://www.psychiatry.org/psychiatrists/practice/dsm/proposed-
changes2T 
 
Anton RF. Naltrexone for the management of alcohol dependence. N Engl J Med. 
2008;359(7):715–721. doi:10.1056/NEJMct0801733 
 
Aron A, Aron EN, Smollan D (1992) Inclusion of Other in the Self Scale and the structure of 
interpersonal closeness. Journal of Personality and Social Psychology 63: 596–612. 
 
Boelen, Paul A., et al. "Prolonged grief disorder, depression, and posttraumatic stress disorder 
are distinguishable syndromes." Journal of affective disorders 125.1-3 (2010): 374-378. 
 
Bolton M, Hodkinson A, Boda S, et al. Serious adverse events reported in placebo randomised 
controlled trials of oral naltrexone: a systematic review and meta-analysis. BMC Med. 
2019;17(1):10. Published 2019 Jan 15. doi:10.1186/s12916-018-1242-0 
 
Bryant RA, Andrew E, Korgaonkar MS (2020). Distinct neural mechanisms of emotional 
processing in prolonged grief disorder. Psychological Medicine 1–9. 
2Thttps://doi.org/10.1017/S00332917190035072T 
 
Bryant RA, Kenny L, Joscelyne A, et al. Treating prolonged grief disorder: a randomized clinical 
trial. JAMA Psychiatry. 2014;71(12):1332–1339. doi:10.1001/jamapsychiatry.2014.1600 
 
Bui E, Nadal-Vicens M, Simon NM. Pharmacological approaches to the treatment of 
complicated grief: rationale and a brief review of the literature. Dialogues Clin Neurosci. 
2012;14(2):149–157. 
 
Cohen, S., Mermelstein, R., Kamarck, T., & Hoberman, H. M. (1985). Measuring the functional 
components of social support. In Social support: Theory, research and applications (pp. 73–94). 
Springer. 
 
Chick J, Anton R, Checinski K, et al. A multicentre, randomized, double-blind, placebo-
controlled trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcohol. 
2000;35(6):587–593. doi:10.1093/alcalc/35.6.587 
 
Hendershot CS, Wardell JD, Samokhvalov AV, Rehm J. Effects of naltrexone on alcohol self-
administration and craving: meta-analysis of human laboratory studies. Addict Biol. 
2017;22(6):1515–1527. doi:10.1111/adb.12425 
 
Holland JM, Graves S, Klingspon KL, Rozalski V. Prolonged grief symptoms related to loss of 
physical functioning: examining unique associations with medical service utilization. Disabil 
Rehabil. 2016;38(3):205–210. doi:10.3109/09638288.2015.1031830 
 
Inagaki TK, Hazlett LI, Andreescu C. Opioids and social bonding: Effect of naltrexone on 
feelings of social connection and ventral striatum activity to close others. J Exp Psychol Gen. 
2020;149(4):732–745. doi:10.1037/xge0000674 
 


Protocol # 20-04021873 
6/18/21 
 
Page # 36 
 
Inagaki TK, Ray LA, Irwin MR, Way BM, Eisenberger NI. Opioids and social bonding: naltrexone 
reduces feelings of social connection. Soc Cogn Affect Neurosci. 2016;11(5):728–735. 
doi:10.1093/scan/nsw006 
 
Kakarala S, et al. The Neurobiological Reward System in Prolonged Grief Disorder (PGD): A 
Systematic Review. 2020. Submitted for publication. 
 
Klein JW. Pharmacotherapy for Substance Use Disorders. Med Clin North Am. 
2016;100(4):891–910. doi:10.1016/j.mcna.2016.03.011 
 
Lannen PK, Wolfe J, Prigerson HG, Onelov E, Kreicbergs UC. Unresolved grief in a national 
sample of bereaved parents: impaired mental and physical health 4 to 9 years later. J Clin 
Oncol. 2008;26(36):5870–5876. doi:10.1200/JCO.2007.14.6738 
 
Maciejewski, P. K., Maercker, A., Boelen, P. A., & Prigerson, H. G. (2016). “Prolonged grief 
disorder” and “persistent complex bereavement disorder”, but not “complicated grief”, are one 
and the same diagnostic entity: an analysis of data from the Yale Bereavement Study. World 
Psychiatry, 15(3), 266–275. 
 
O'Connor MF, Wellisch DK, Stanton AL, Eisenberger NI, Irwin MR and Lieberman MD. (2008) 
Craving love? Enduring grief activates brain's reward center. Neuroimage 42, 969-72. 
 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266–1277. doi:10.1176/appi.ajp.2011.10111704 
 
Prigerson HG, Bierhals AJ, Kasl SV, et al. Traumatic grief as a risk factor for mental and 
physical morbidity. Am J Psychiatry. 1997;154(5):616–623. doi:10.1176/ajp.154.5.616  
 
Prigerson HG, Horowitz MJ, Jacobs SC, et al. Prolonged grief disorder: Psychometric validation 
of criteria proposed for DSM-V and ICD-11 [published correction appears in PLoS Med. 2013 
Dec;10(12). doi:10.1371/annotation/a1d91e0d-981f-4674-926c-0fbd2463b5ea. Bonanno, 
George [corrected to Bonanno, George A]]. PLoS Med. 2009;6(8):e1000121. 
doi:10.1371/journal.pmed.1000121 
 
Prigerson HG, Boelen PA, Xu J, Smith KV, Maciejewski PK. Validation of the newly proposed 
DSM criteria for prolonged grief disorder and the PG-13-Revised (PG-13-R) scale. World 
Psychiatry. 2021. 
 
Reynolds CF 3rd, Miller MD, Pasternak RE, Frank E, Perel JM, Cornes C et al. 1999. Treatment  
of bereavement-related major depressive episodes in later life: a controlled study of acute and 
continuation treatment with nortriptyline and interpersonal psychotherapy. Am. J.Psychiatry 156: 
202–208. 
ReviaP®
P (naltrexone) [US package insert]. Duramed Pharmaceuticals, Inc; Pomona, New York; 
2013 
 
Shear MK, Frank E, Houck P, Reynolds CF., III Treatment of complicated grief: randomized 
controlled trial. JAMA. 2005;293:2601–2659. 
 
Stahl, S. M. (2014). Prescriber’s guide: Stahl’s essential psychopharmacology (5th ed.). New 


Protocol # 20-04021873 
6/18/21 
 
Page # 37 
 
York: NY: Cambridge University Press. 
 
Towers CV, Katz E, Weitz B, Visconti K. Use of naltrexone in treating opioid use disorder in 
pregnancy. Am J Obstet Gynecol. 2020;222(1):83.e1–83.e8. doi:10.1016/j.ajog.2019.07.037 
 
Trevino KM, Litz B, Papa A, et ahospitall. Bereavement Challenges and Their Relationship to 
Physical and Psychological Adjustment to Loss. J Palliat Med. 2018;21(4):479–488. 
doi:10.1089/jpm.2017.0386 
 
Tsai, J., & Rosenheck, R. A. (2012). Conceptualizing social integration among formerly 
homeless adults with severe mental illness. Journal of Community Psychology, 40(4), 456–467. 
 
Zuckoff A, Shear K, Frank E, Daley DC, Seligman K, Silowash R. Treating complicated grief and 
substance use disorders: a pilot study. J Subst Abuse Treat. 2006;30(3):205–211. 
doi:10.1016/j.jsat.2005.12.001 
 
Zygmont M, Prigerson HG, Houck PR, et al. A post hoc comparison of paroxetine and 
nortriptyline for symptoms of traumatic grief. J Clin Psychiatry. 1998;59(5):241–245. 
doi:10.4088/jcp.v59n0507