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Gang et al. Trials(2021) 22:110A second reason for finding an alternative to SSRIs forthe treatment of PGD is that they take weeks to monthsto achieve full efficacy. Persons suffering from PGD wouldbenefit from faster acting interventions, especially givensignificant suicide attempt risk of those meeting criteriafor PGD [17]. A delay in resolution of PGD symptomswould protract the period of risk for suicidal thoughts andbehaviors with which PGD is associated [4, 17].Neurobiologically, numerous studies suggest that thereare associations between symptoms of PGD and thereward pathway, which is the same pathway primarilyresponsible for addiction [16]. The reward pathwayrefers to a group of interconnected structures in thebrain that uses dopamine as a signal to modulate theexperience of reward. Some pertinent examples ofenhanced activation in brain structures in PGD that arealso important to the reward pathway include thenucleus accumbens [18] and orbitofrontal cortex [15].Based on evidence supporting an association betweenPGD and neurobiological correlates of reward andaddiction, we hypothesize that treatments for addictionmight prove successful where those of MDD and PTSDhave failed. Currently, disorders of addiction are treatedwith a wide variety of medications based upon thesubstance being abused, including bupropion andvarenicline for tobacco use; naltrexone and acamprosatefor alcohol use; methadone and buprenorphine for opioiduse [19]. Of these, we have opted to trial naltrexone totreat PGD because of its mechanism of action, effects onsocial attachment, and side-effect profile.Mechanistically, naltrexone is a competitive antagonistof opioid receptors. These receptors, when bound byendogenous opioids released in response to rewardingstimuli, normally cause the subsequent release ofdopamine in the reward pathway. Therefore, naltrexonemay be an appropriate choice to treat PGD, as itsmechanism of action directly affects the reward pathway;by blocking opioid receptors, release of dopamine in thereward pathway is inhibited. It also has two practicaladvantages for patients. First, it can be administeredorally (daily) or intramuscularly (monthly). Second, costof oral naltrexone is not prohibitively high and is oftencovered by insurance [20].Symptomatically, naltrexone targets two crucial aspectsof PGD. First, assuming that having and maintainingsocial connections is vital to human functioning, theopioid theory of social attachment suggests thatendogenous opioids are released during these experiencesof social bonding, which then underlie the pleasantfeelings of social bonding to positively reinforce theformation of such bonds. Based on this theory, studieshave shown that naltrexone reduces feelings of socialconnection, especially to one’s closest others [21, 22].Reduced positive associations with significant others,Page 3 of 15especially the deceased, may make bereavement feel lesslonely and isolated while diminishing the reward derivedfrom reminiscing about the deceased. Second, metaanalysis confirms that naltrexone reduces craving in patients with alcohol dependence [23]; in PGD, craving thedeceased is the core symptom [5]. Thus, naltrexone mayreduce the craving for the deceased and thereby severityof PGD. Given these findings, we predict that naltrexonewill provide a pharmacological way to dampen the benefits of social bonding while reducing the yearning or craving for the deceased loved one, which would reduce theseverity of PGD.With respect to side effects, naltrexone is welltolerated and may be better tolerated than TCAs orSSRIs. The most common side effects of naltrexone include nausea, vomiting, abdominal pain, headache, andfatigue. The most severe side effect warranting an FDAblack-box warning is hepatotoxicity; in the COMBINEstudy, elevations in liver function tests (LFTs) were seenin only 11 of 614 participants, with most normalizingafter cessation and no serious long-term consequences[24]. In addition, although naltrexone can cause suddenand severe withdrawal in opiate users, we would not trialnaltrexone in bereaved individuals who are opiate users.Objectives {7}The primary objective is to determine the efficacy ofnaltrexone in reducing PGD symptoms compared toplacebo.Secondary objectiveThe secondary objective is to evaluate the effects ofnaltrexone on social closeness with both the deceased(the bereaved person) and the living (surviving othersand social network).Exploratory objectives To evaluate associations between naltrexone andsocial integration and social connectedness. To evaluate associations between naltrexone andsuicidal thoughts and behaviors. To evaluate associations between naltrexone andhealth behaviors (e.g., alcohol and tobacco use,sleep, food consumption). To evaluate associations between outcomes ofCOVID-19-related deaths versus other causes ofdeath.Trial design {8}This study is designed as a randomized, placebocontrolled, triple-blinded (to healthcare professionals,participants, and data analysts), stage IV, single-site superiority trial with two parallel groups.

Gang et al. Trials(2021) 22:110Methods: participants, interventions andoutcomesStudy setting {9}The study will take place at NewYork Presbyterian –Weill Cornell Medicine (NYP-WCM) in New York, NY,USA.Eligibility criteria {10}Inclusion criteria1. 18 years of age or older and younger than 90 yearsof age.2. Lives within a reasonable distance from NYP-WCMfor convenient clinic visits.3. Can speak, read, and write English proficiently.4. Meet diagnostic criteria for PGD based on/consistent with the DSM criteria (AmericanPsychiatric Association, n.d.), which includes:a. Death of a person the bereaved survivorconsidered a significant other.b. Since the death, there has been a grief responsecharacterized by intense yearning/longing forthe deceased person or a preoccupation withthoughts or memories of the deceased personpresent nearly every day for the last month.c. As a result of the death, at least 3 of thefollowing symptoms have been experiencednearly every day, for at least the last month:identity disruption (e.g., feeling as though partof oneself has died); marked sense of disbeliefabout the death; avoidance of reminders thatthe person is dead; intense emotional pain (e.g.,anger, bitterness, sorrow) related to the death;difficulty moving on with life (e.g., problemsengaging 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 female, must agree to use a method ofcontraception and be willing and able to continuecontraception during the first 8 weeks of the studywhile taking the study drug. Female patients whoare planning to use oral hormonal contraceptionduring this time must have initiated it at least 2months prior to the baseline visit.6. If male, must agree to use a method ofcontraception and be willing and able to continuecontraception during the first 8 weeks of the studywhile taking the study drug.Exclusion criteria1. Having recently started taking/prescribedmedications for any psychiatric illness (e.g., SSRIsPage 4 of 15for MDD) within the past 3 months; participantswho have been taking this medication for longerthan 3 months can be included.2. Having recently started psychotherapy for anypsychiatric illness within the past 3 months;participants who have been receiving psychotherapyfor longer than 3 months can be included.3. Prior history of recently active (e.g., within the past3 months) opioid dependence.4. Current prescription, non-prescription, or illicit opioid use (i.e., acute use within the past 14 days orchronic 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 otherclinically relevant medication that has potential tocause liver injury with concurrent use of naltrexone.7. Currently pregnant, lactating, or planning tobecome pregnant during the study.8. Active hepatitis or liver disease.9. Alanine aminotransferase (ALT) or aspartateaminotransferase (AST) levels more than onestandard deviation above the upper limit of normalon initial laboratory examination.10. Screen positive for active suicidal thoughts orbehaviors.Who will take informed consent? {26a}Written informed consent will be obtained fromparticipants by trained research assistants at the firstvisit. During the informed consent process, the studystaff obtaining consent will review the study in detailallowing for the participant to interject with questions atany time during the discussion. The main points thatwill be addressed by the study personnel obtaininginformed consent include explaining why the currentresearch study is being conducted, the sources offunding for the project and what purpose the proposedresearch serves. Additionally, the subject will be madeaware of who is responsible for conducting the researchand how subjects are selected for participation in theresearch.The study staff will explain in explicit detail what willbe asked of the participant if he/she agrees to participatein the study and estimate the potential timecommitment involved. Participant will know what his/her responsibilities will entail, what risks or benefits maybe involved, and what potential costs could be incurred

Gang et al. Trials(2021) 22:110should they agree to participate. Study staff willunderscore the importance placed upon maintainingparticipant confidentiality, as well as participant’s rightswhile involved in the study, which includes the right towithdraw participation at any time during the researchsince their participation is entirely voluntary in nature.The informed consent form will also contain a sectiondedicated to explaining what constitutes protectedhealth information and how this information remainsconfidential per HIPAA (Health Insurance Portabilityand Accountability Act) guidelines. Finally, the informedconsent form will provide contact information for boththe principal investigators as well as the Office for theProtection of Research Subjects. All informed consentprocesses will adhere to the policies set forth by theInstitutional Review Board.Additional consent provisions for collection and use ofparticipant data and biological specimens in ancillarystudies, if applicable. {26b}Participant data and biological specimens will not beused in ancillary studies.InterventionsExplanation for the choice of comparators {6b}Placebo was chosen as control in this study, for tworeasons: (1) the presence of a placebo mitigates theplacebo effect, and (2) as a new disorder, there is nostandard of care treatment for PGD; thus, most patientsin real life are, by default, not receiving treatment at all[10].Intervention description {11a}Naltrexone HCl 50 mg is an oral medication in tabletform purchased from an FDA-licensed drug wholesaler.Naltrexone will be compounded and over-encapsulatedinto a gelatin capsule stable for 6 months at roomtemperature with instruction to be taken as is PO with aglass of water. Placebo, composed of a filler material(e.g., lactose or methyl cellulose), will be identical in appearance to naltrexone via over-encapsulation. The tablets are packaged into white, high-density polyethylenebottles fitted with child-resistant closures with foil induction seals, each containing 56 tablets. Each bottlealso contains a polyester coil as bottle filler. Bottles willbe labeled as such that only the FDA-licensed drugwholesaler will know which ones contain naltrexone andwhich ones contain placebo; this information will onlybe shared with the principal investigator (PI).All participants will take their assigned medicationdaily for 8 weeks, starting the day after their first clinicvisit. This medication will be dispensed once during thisfirst clinic visit. For naltrexone, the daily dose will be 50mg. Participants will be advised to take it aroundPage 5 of 15lunchtime, but this is not a strict requirement;naltrexone can be taken with or without food. There isno anticipated adverse reaction from stoppingnaltrexone at any point in the study; therefore, there isno maximum or minimum duration. If participants missa dose, they can resume the normal schedule the nextday; there is no need to compensate for any misseddoses.Criteria for discontinuing or modifying allocatedinterventions {11b}An investigator may discontinue or withdraw aparticipant from the study for the following reasons: Pregnancy Significant study intervention non-compliance. If any clinical adverse event (AE), laboratory abnormality (e.g., elevated LFTs), or other medicalcondition or situation occurs such that continuedparticipation in the study would not be in the bestinterest of the participant.Disease progression which requires discontinuationof the study interventionIf the participant meets an exclusion criterion(either newly developed or not previouslyrecognized) that precludes further studyparticipation.Participant loses medication.Participant lost to follow-up after 3 attempts to contact subject to schedule study visit.Participant requests withdrawal of participation.Strategies to improve adherence to interventions {11c}Adherence to protocol will be indicated by attending allvisits and taking at least 80% of their medication. Threeconsecutive daily attempts during the week of thescheduled visit will be made to reschedule a participant’svisit. Medication compliance will be evaluated bycounting returned tablets; participants will be asked tobring their bottle of medication at every visit.Participants will also be asked if there was any difficultyin taking the medication during each visit. Adherencewill be tracked in a drug accountability log.Relevant concomitant care permitted or prohibitedduring the trial {11d}Participants receiving concomitant psychotherapy and/or pharmacotherapy for any psychiatric illness will bescreened out unless they have been receiving saidtherapy for at least 3 months before enrolling in thestudy. This provision is to ensure that previous therapyhas stabilized and therefore will not interfere orconfound the effect of naltrexone on PGD.

Gang et al. Trials(2021) 22:110Concomitant use of medications known to cause liverdamage, as outlined in the exclusion criteria (section“Criteria for discontinuing or modifying allocatedinterventions {11b}”), are not allowed to be used duringthe study due to concern of potentiated liver injury withconcurrent use of naltrexone.Provisions for post-trial care {30}If a participant experiences injury from known orunknown risks of the research procedures as described,immediate medical care and treatment, includinghospitalization, if necessary, will be available at the usualcharge for such treatment.If the participant screens positive for serious suicidalintent with or without a plan, we will have a licensedmental health professional (e.g., psychiatrist, psychologist)more fully evaluate suicidality and make arrangements forthe participant to get to a local hospital emergency roomif serious risk is imminent. If not at imminent risk but SIwas endorsed, we will refer them to a licensed mentalhealth professional.No monetary compensation for injury is available.Outcomes {12}Primary outcome measuresDifference in PGD symptom severity between the twotreatment arms will be measured by using StructuredClinical Interview for PGD (SCIP) and Prolonged Grief13-Revised (PG-13-R). SCIP will be administered to participants during each clinic visit (weeks 1, 4, and 8). PG13-R will be administered weekly (weeks 1–12). Giventhat both these measures are scored, changes in thescore from baseline will be analyzed.Secondary outcome measuresDifference in the strength of subjectively perceivedcloseness of a social relationship between the twotreatment arms will be measured by the Inclusion of theother in the Self (IOS) Scale. This scale will beadministered at every clinic visit (weeks 1, 4, and 8), aswell as at follow-up (week 12). Changes in the numericalstrength value from baseline will be analyzed. Measuringsocial closeness to the deceased is important as wehypothesize that naltrexone will help the bereaved to detach from the deceased. In turn, detachment from thedeceased is a necessary first step towards being able toconnect with living others.Exploratory outcome measuresDifference in social integration and social connectednessbetween the two treatment arms will be measured bythe Social Integration Questionnaire (SIQ), InterpersonalSupport Evaluation List (ISEL), and the SocialConnectedness Survey (SCS). All these measures will bePage 6 of 15administered at every clinic visit (weeks 1, 4, and 8), aswell as at follow-up (week 12). Measuring social integration is important as we hypothesize that after being detached form the deceased, participants are better able tosocially connect with others. In addition, social supportcan influence the bereavement process and thus PG-13R scores.Differences in SI between the two treatment arms willbe measured by the Columbia-Suicide Severity RatingScale (C-SSRS) at every clinic visit (weeks 1, 4, and 8), aswell as at follow-up (week 12). SI is monitored for tworeasons: (1) suicide, attempted suicide, and SI have beenreported in the post-marketing experience with naltrexone in the use of opioid dependence although no causalrelationship has been demonstrated; (2) given that PGDis associated with increased risk of suicide, decreases inPGD symptom severity may correspond to decreased SI.Differences in health behaviors (e.g., smoking history,alcohol history, health perception, and health-promotingbehaviors) between the two treatments arms will bemeasured by a standard self-reported questionnairemonthly at every clinic visit (weeks 1, 4, and 8), as wellas at follow-up (week 12). Bereaved individuals havebeen shown to exhibit negative changes in health behaviors post-loss [25].Participant timeline {13}A schema of this trial is presented in Fig. 1. The totalstudy duration for participants will be 12 weeks. Thefirst 8 weeks are when participants will be taking theirassigned medication and attending three clinic visitsevery 4 weeks. Participants will then be followed up 4weeks from their last clinic visit.A timeline of assessments is provided in Table 1.Participants will initially be screened over the telephone.If deemed eligible, they will be scheduled for their firstclinic visit (day 0) ideally within a week of the telephonescreen. During their first clinic visit, participants will beclinically interviewed to determine diagnosis of PGD viaSCIP, screened for SI and behavior via the C-SSRS, andverify their past medical history to confirm eligibility. Ifconfirmed eligible, written informed consent will thenbe obtained (Fig. 2). Participants will then fill out questionnaires regarding their sociodemographic information; current medications; social closeness, integration,and connectedness; and health behaviors. During thisvisit, participants will be asked to provide a sample ofblood and undergo a urine pregnancy test if applicable.At the end of the visit, participants will be dispensedtheir 8-week supply of medication from the investigational pharmacy.Participants’ second clinic visit will take place 28 daysfrom their first visit. Like their first visit, participantswill be clinically interviewed for PGD, screened for

Gang et al. Trials(2021) 22:110Page 7 of 15Fig. 1 Schemasuicide, review any changes to medications, fill outquestionnaires, have their blood drawn, and undergo aurine pregnancy test if applicable. Starting from theirsecond visit, participants will be asked about any sideeffects, and the number of remaining tablets will becounted to determine treatment adherence.Participants’ third clinic visit will take place 28 daysfrom their second visit and will consist of the samecomponents as their second visit. At the end of this visit,participants will be asked to return any leftovermedication.Follow-up will occur 28 days from their third clinicvisit via online assessments that are emailed toparticipants to complete. These online assessmentsinclude a review of side effects; a survey of PGDsymptoms; questionnaires regarding social closeness,integration, and connectedness; and health behaviors.Additionally, during the 12 weeks, participants will beemailed weekly surveys of PGD symptoms.Sample size {14}According to previous studies tracking grief intensitychanges across time among the bereaved sample [5, 26], weestimate a natural decline of 1.0 in PG-13-R scores during aperiod of 2 months with a standard deviation of 6.0, for patient

Methods/design: This is a randomized, placebo-controlled, triple-blinded (to healthcare professionals/study staff, participants, and data analysts) study in which we propose to enroll 48 participants who meet criteria for Prolonged Grief Disorder (PGD). Participants will be randomly assigned to the naltrexone 50mg oral arm or placebo arm;