Ignite Creation Date:
2024-05-11 @ 8:30 AM
Last Modification Date:
2024-10-26 @ 3:29 PM
Study NCT ID:
NCT06408714
Status:
RECRUITING
Last Update Posted:
2024-05-17
First Post:
2024-05-07
Brief Title:
Nalmefene vs Naloxone for the Treatment of Recurrent Respiratory Depression After Opioid Overdose
Sponsor:
University of New Mexico
Organization:
University of New Mexico
Study Overview
Official Title:
Comparison of Nalmefene Hydrochloride Injection and Naloxone Hydrochloride Injection for the Treatment of Recurrent Respiratory Depression After Suspected Acute Opioid Overdose in the Emergency Department
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The goal of this clinical trial is to compare naloxone to nalmefene for the treatment of opioid overdose in adults The main questions it aims to answer are
Does nalmefene lower the number of doses of medicine participants need to treat opioid overdose
When participants are given nalmefene instead of naloxone do they have fewer complications of opioid overdose such as being admitted to the hospital or having a breathing tube inserted
Researchers will compare nalmefene to naloxone for the treatment of opioid overdose Nalmefene and naloxone are both approved medicines to treat opioid overdose
Participants who are brought to the emergency department after an opioid overdose will be given a dose of either nalmefene or naloxone if their breathing slows down again after an opioid overdose Participants will
Stay in the emergency department for 8 hours after receiving a dose of nalmefene or naloxone
Receive a phone call 7 days after their emergency department to check on how they are doing
Background information
Naloxone also known as Narcan and nalmefene are opioid blocking medicines When someone overdoses on an opioid such as heroin or fentanyl their breathing slows down or stops and they can die By giving naloxone or nalmefene the effect of the opioid can be blocked and the person can start breathing again Naloxone is the most commonly used medicine to reverse an opioid overdose The effect of naloxone lasts about an hour and patients may need more than one dose of naloxone to keep them breathing Sometimes patients overdose get a dose of naloxone and wake up and then some time later their breathing slows down again and they need another dose of naloxone This can happen because the effect of the opioid they took lasts longer than the effect of the naloxone
The effect of nalmefene lasts longer than naloxone about four hours If a person gets nalmefene their opioid may wear off before the nalmefene wears off and they might not need any more doses of a reversal medicine Both naloxone and nalmefene are approved medicines for treating opioid overdose
Often when a person overdoses on an opioid someone gives them naloxone right away and then they are brought to the emergency department In the emergency department they are watched for several hours to make sure they dont stop breathing again when their naloxone wears off If they do stop breathing again they are given another dose of naloxone In this study participants will be given either nalmefene or naloxone if their breathing slows down while they are in the emergency department
Does nalmefene lower the number of doses of medicine participants need to treat opioid overdose
When participants are given nalmefene instead of naloxone do they have fewer complications of opioid overdose such as being admitted to the hospital or having a breathing tube inserted
Researchers will compare nalmefene to naloxone for the treatment of opioid overdose Nalmefene and naloxone are both approved medicines to treat opioid overdose
Participants who are brought to the emergency department after an opioid overdose will be given a dose of either nalmefene or naloxone if their breathing slows down again after an opioid overdose Participants will
Stay in the emergency department for 8 hours after receiving a dose of nalmefene or naloxone
Receive a phone call 7 days after their emergency department to check on how they are doing
Background information
Naloxone also known as Narcan and nalmefene are opioid blocking medicines When someone overdoses on an opioid such as heroin or fentanyl their breathing slows down or stops and they can die By giving naloxone or nalmefene the effect of the opioid can be blocked and the person can start breathing again Naloxone is the most commonly used medicine to reverse an opioid overdose The effect of naloxone lasts about an hour and patients may need more than one dose of naloxone to keep them breathing Sometimes patients overdose get a dose of naloxone and wake up and then some time later their breathing slows down again and they need another dose of naloxone This can happen because the effect of the opioid they took lasts longer than the effect of the naloxone
The effect of nalmefene lasts longer than naloxone about four hours If a person gets nalmefene their opioid may wear off before the nalmefene wears off and they might not need any more doses of a reversal medicine Both naloxone and nalmefene are approved medicines for treating opioid overdose
Often when a person overdoses on an opioid someone gives them naloxone right away and then they are brought to the emergency department In the emergency department they are watched for several hours to make sure they dont stop breathing again when their naloxone wears off If they do stop breathing again they are given another dose of naloxone In this study participants will be given either nalmefene or naloxone if their breathing slows down while they are in the emergency department
Detailed Description:
1 Study Design This is an open-label prospective randomized single center study comparing nalmefene to naloxone in the treatment of recurrent respiratory depression from opioids
2 Number of Subjects
We will enroll 37 patients in the nalmefene group and 37 patients in the naloxone group for a total of 74 patients
Based upon our feasibility study of naloxone administrations in the ED 344 patients received naloxone in the ED during a two-year period 2021-2022 corresponding to approximately 14 patients per month Note that this is likely their 2nd dose of naloxone as nearly all patients arrive via EMS and we presume received naloxone by EMS We estimate that 75 of patients who receive opioid antagonist treatment during EMS transport or shortly after ED arrival will be capable of providing informed consent in the ED We estimate that up to 50 may decline to participate Based on these parameters we estimate enrolling 54 patients per month or 96 subjects over the 18 month enrollment period
In our power and sample size analysis we estimated we would need to enroll 62 subjects We added a 20 increase in our sample size to account for subjects that might not stay for the observation period for a total of 74 patients
To enroll 74 patients we will screen 220 patients for eligibility and consent
Sample size justification
We conducted power analyses with varying scenarios for a noninferiority clinical trial comparing nalmefene versus naloxone For a redosing rate p1 of 033 for naloxone and a redosing rate p2 of 005 for nalmefene a significance level alpha of 0025 and a margin of noninferiority of -002 we would need 31 patients in each respectively This would give us a total of 62 patients to achieve a power of 08 We will enroll 20 extra patients or 37 patients in each group in anticipation of patients not completing the observation period or the study for a total of 74 patients
3 Study Timelines
The duration of an individual subjects participation in the research 7 days
Initial visit emergency department visit with observation of 8 hours after emergency department arrival or until discharge whichever comes first
Second evaluation phone follow up at 7 days
The duration anticipated to enroll all subjects 15 years
8 Research Setting Study site Single center study at the University of New Mexico Hospital Adult Emergency Department UNMH is the only academic medical center Level I trauma center and stroke center in New Mexico UNMH is also the safety net hospital for the greater Albuquerque area The UNMH ED saw over 102000 patients in 2022 of whom 58000 were seen in the adult ED
Biological samples will be processed by TriCore Laboratories the contracted laboratory service for UNM HSC Xylazine and nitazene testing will be performed at NMS Labs nmslabscom
9 Resources Available
The UNMH emergency department is staffed 24 hours a day with licensed emergency physicians attending physicians Attending physicians will be responsible for medical decision-making and ordering and evaluation of necessary diagnostics and therapeutics for study participants
Resources
The Department of Emergency Medicine maintains a workforce of full-time trained research staff specializing in research subject identification and recruitment All staff are trained in human subject research good clinical practices and Basic Science Laboratory level 1 and 2 BSL 1-2 procedures Staff are able to accommodate regular night and weekend coverage to ensure adequate staffing to respond to potential subject enrollments
All study personnel are required to maintain current human subject protections and good clinical practices certifications and complete and document study specific training and delegation on study training and delegation logs
Pharmacy Resources The UNMH investigational drug service is used in this study The investigational drug service allows for the secure storage and dispensation of investigational drugs in accordance with applicable state and federal regulations and institutional policies
Laboratory resources The UNM HSC Clinical and Translational Sciences Center CTSC contract laboratory will be used for the processing and storage of research samples The CTSC contract laboratory provides secure 24-hour access to calibrated continuous temperature monitored freezers centrifuge and BSL-2 lab bench space Quanititative Nalmefene and Xylazine testing will be performed by NMS labs
12 Study Procedures
Screening Study subjects will be recruited from the University of New Mexico Hospital Emergency Department Research Assistants RAs will identify patients seen in the ED by reviewing the electronic medical record EMR tracking board notification by secure messaging system of arriving patients and by provider referral
Informed Consent Patients who are determined to meet all inclusion and none of the exclusion criteria will be approached about informed consent by a trained IRB-approved study team member For additional detail on informed consent see Section 21 Consent Process
Enrollment and Randomization Patients who provide written informed consent are considered enrolled in the study Subjects will be asked to complete demographics medical history and prior and concomitant medications by survey at the time of enrollment Blood Alcohol Content BAC will be measured by Breathalyzer Participants will then be randomized using the UNM Health Sciences REDCap randomization tool to either nalmefene or standard care naloxone treatment arms Research staff will be blinded to randomization
Blood Collection Blood collection for serum testing for co-ingestants xylazine and nitazenes will be performed after enrollment Blood collection for research testing will involve no more than 15 mL 1 tablespoon in up to 3 tubes at one timepoint
Subject Follow-Up RAs will remain present with the patient in the peri-dosing period to observe and record any adverse events including any occurrence of precipitated withdrawal or recrudescence for no less than 8 hours after emergency department arrival or until emergency department discharge whichever comes first Subjects will be contacted by phone 7 days - 2 days after enrollment to assess for recurrence of opioid overdose symptoms repeat emergency department visits or hospitalizations and occurrence of adverse events
Data Acquisition Demographics medical history and prior and concomitant medications adverse events will be collected by subject interviewsurvey andor observation in the ED All other data elements such as details related to medication laboratory and imagining results diagnosis and information on subsequent discharge andor hospitalization or return visit to the emergency department will be captured from the subjects EMR
13 Data Analysis Plan We will use an intention-to-treat analysis For the primary outcome we will compare the proportion of subjects experiencing the primary endpoint respiratory depression requiring opioid antagonist treatment using the Newcombes method for the difference between two proportions1 adjusted for a non-inferiority framework as the initial analysis
As we expect that the time to event respiratory depression will differ between the two treatment arms we will also compare the risk of recurrent respiratory depression using a failure time analysis Failure time analysis also known as survival analysis allows us to assess the risk of a failure event here recurrent respiratory depression while adjusting for observations that are time dependent and of varying length Failure time analyses also correctly account for incomplete observations because of a study ending or loss of subjects to follow-up we anticipate that some subjects may not stay for the full observation period For the initial analysis we anticipate using nonparametric techniques such as Kaplan-Meier curve estimation and log-rank tests to assess for differences in recurrent respiratory depression between the two arms Most frequently failure time analysis is used in situations where only one event occurs such as a diagnostic endpoint disease cure or death and the subject then is withdrawn from the study In the proposed study subjects can experience multiple failure events recurrent episodes of respiratory depression because a rescue therapy naloxone or nalmefene is available After completing the initial non-parametric analyses we propose an additional analysis that will allow us to take advantage of the likelihood that subjects may have more than one endpoint Since multiple events can occur within the same subject calculation of standard errors and statistical inference need to account for the correlation between observations in the same individual The method we propose using does this precisely and we have used this method for a different poisoningantidote study23 With this method the point estimate of the relative risk is not affected by the correlation between repeat measurements within the same individual and therefore can be calculated using a proportional hazards model All analyses will use the R statistical language
14 Provisions to Monitor the Data to Ensure the Safety of Subjects Data monitor services will be provided by the University of New Mexico Hospitals Clinical Trials Operations Office and supervised by Leslie Byatt BA CCRC PCP The study data monitor is not directly affiliated with the study
Safety monitoring will be provided by Snehal Bhatt MD Dr Bhatt is an experienced addiction medicine physician Dr Bhatt is affiliated with the University of New Mexico School of Medicine
All study subjects will be asked to stay in the UNMH Emergency Department for the duration of the 8 hour observation period All adverse events will be recorded for the duration of the 8 hour observation period All adverse event information will be prepared in summary deidentified and provided to the safety monitor on the following schedule for review
Review 1 After completion of the 3rd subject enrollment 4 of subjects enrolled Review 2 After completion of the 10th subject enrollment 14 of subjects enrolled Review 3 After completion of the 26th subject enrollment 35 of subjects enrolled Review 4 After completion of the 42nd subject enrollment 57 of subjects enrolled Review 5 After completion of the 74th and final subject enrollment 100 of subjects enrolled This safety monitor review schedule is subject to change in the event that the safety monitor raises concerns that merit more frequent reviews
All serious adverse events will be gathered through the day 7 follow-up In the event of a serious adverse event SAE that is determined to be unexpected and possibly or probably related to the investigational product enrollment will be temporarily stopped until the safety monitor has reviewed and provided recommendations related to ongoing study conduct Once any recommendations if any have been addressed the study may continue Initial SAE reports have to be reported within 24 hours of the identification of an SAE follow-up attempts will be made as needed within 3 days or no later than 14 days from the initial report if additional information becomes available this will be processed as per our procedures All SAEs will be followed to resolution All SAE information will be gathered in a detailed summary report and transmitted to the safety monitor for review Only SAEs will be forwarded to Drug Safety mailbox at AEreport2pharmacom The investigator will be using the following definitions for AEs SAEs and reportable new information The SAE report from will include start and stop date whether or not it was unexpected concise identification according to the Common Terminology for the Categorization of Adverse Events CTCAE detailed narrative description including why it is determine to meet the SAE definition below any medical interventions to address the SAE the events relationship to the study intervention and report type initial follow-up or final All SAEs must be reviewed by the principal investigator prior to submission to the safety monitor for review
Adverse Event AE Any untoward or unfavorable medical occurrence in a human study participant including any abnormal sign eg abnormal physical exam or laboratory finding symptom or disease temporally associated with the participants involvement in the research whether or not considered related to participation in the research
Serious Adverse Event SAE Any adverse event that
Results in death
Is life threatening or places the participant at immediate risk of death from the event as it occurred
Requires or prolongs hospitalization
Causes persistent or significant disability or incapacity
Results in congenital anomalies or birth defects
Is another condition which investigators judge to represent significant hazards
A pregnancy is not by definition an SAE but is handled as an SAE because it is not a condition that should occur during the clinical trial requires the subject to be discontinued from the study and requires ongoing monitoring of the pregnancy by the PI Abnormal pregnancy outcomes are considered as reportable SAEs SAEs associated with pregnancy outcome include but are not limited to
Pregnancy losses eg spontaneous abortion late fetal death elective termination
Life-threatening developments eg placental abruption fetal distress Congenital anomalies
Neonatal fatality any event resulting in maternal hospitalization prolonged hospitalization or maternal fatality
Any female subject who becomes pregnant while participating will be withdrawn from the study but will be contacted to determine the pregnancy outcome
The study team will promptly report all unanticipated problems that meet the following criteria to the UNM HSC HRRC within 5 business days of identification as reportable information Defined by DHHS 45 CFR part 46 as 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 IRB-approved research protocol and informed consent document and b the characteristics of the study population
related or possibly related to participation in the research in this guidance document possibly related means there is a reasonable possibility that the incident experience or outcome may have been caused by the procedures involved in the research
suggests that the research places participants or others at a greater risk of harm including physical psychological economic or social harm than was previously known or recognized
Subjects in the trial will receive clinical care in the UNM Hospital Emergency Department As subjects are also patients being treated for the effects of opioid intoxication all will receive standard of care Standard care includes establishing intravenous access to provide additional medication to reverse respiratory depression end-tidal carbon dioxide monitoring pulse oximetry electrocardiographic monitoring and vital sign monitoring All subjects will receive care from the ED treatment team The ED team consists of a board-certified EM faculty member resident physicians advanced practice providers emergency medicine pharmacists and registered nurses All subjects in the trial will be treated in appropriate clinical spaces within the ED A full spectrum of standard emergency equipment is readily available eg airway adjuncts advanced monitoring etc
15 Withdrawal of Subjects The study medical clinician must apply their clinical judgement to determine if an adverse event is of sufficient severity to require that the participant be withdrawn from further study participation The study medical clinician should consult with the site Principal Investigator the Co-Investigator andor Medical Monitor as needed If necessary a study medical clinician may suspend any trial treatments and institute the necessary medical therapy to protect a participant from any immediate danger
A participant may also voluntarily withdraw from treatment due to what they perceive as an intolerable adverse event or for any other reason If a voluntary withdrawal is requested the participant will be asked to complete an end-of-medication visit to assure safety and to document end-of-medication outcomes and will be given recommendations for medical care andor referrals to treatment as necessary
A participant may withdraw from any portion of the protocol eg serum collection for expanded toxicology testing but complete other aspects of the study
A participant may withdraw from the study at any time
16 Data ManagementConfidentiality All study data will be stored in accordance with all applicable state and federal regulations and in accordance with institutional requirements All subject source information will be stored NResearch-Studies network drive
The research team will have access to the patients medical record to abstract elements from the patients chart relevant to the study including patient disposition and additional AE and SAEs and 7 day follow-up data
Zip codes will not be recorded Information abstracted as part of the research study will not include direct patient identifiers ie name MRN FIN address Subjects will be identified by a unique study number A link between the patients identifying information will remain secured and stored apart from study data on the N drive This data will include substance abuse information
Data from this study will not be publicly available
All study data will be entered into UNM Health Sciences REDcap a secure web application for building and managing online surveys and databases After study closure all data will be stored in the NResearch-studies network drive
All study specimens will be labeled with a unique study ID only and stored only for the duration of testing described in this protocol Specimens will not be banked for this study and will only be accessible to IRB approved members of the study team
No data will be collected by audio or video recording Data will not include photographs This study is not funded by the NIH Data will be retained for a period of 6 years from the date the study is complete and then destroyed No minors will be included in this study
17 Data and Specimen Banking Neither data nor specimens will be banked for this study
18 Risks to Subjects
Study related risks include medication risks study procedures risks and loss of confidentiality
Medication risks associated with the use of naloxone and nalmefene are very similar and may include precipitation of severe opioid withdrawal recurrent respiratory and central nervous system depression nausea vomiting fever dizziness headache chills and vasodilation relaxingdilation of blood vessels Other risks associated with reversal of opioid overdose include cardiac related risks such as pulmonary edema fluid in the lungs cardiovascular instability hypotension low blood pressure hypertension high blood pressure tachycardia fast heart rate ventricular fibrillation irregular heart beat Risks associated with the use of nalmefene and naloxone in pregnant people include precipitated withdrawal in the fetus
Risks associated with study procedures which include a study blood draw are minimal They include pain bruising infection lightheadedness fainting blood clots and bleeding or other discomforts at the draw site
Risks associated with the possible loss of confidentiality may include emotional discomfort or stress
19 Potential Benefits to Subjects There are no known benefits to subjects
20 Recruitment Methods Potential subjects will be identified for participation in the study after presentation to the UNM ED for suspected acute opioid overdose Based upon our feasibility analyses we expect that most subjects will arrive via EMS Our dispatch team uses a secure text messaging system TigerConnect httpstigerconnectcom to alert designated staff members of pending patient arrivals based off EMS radio reports These messages typically provide a very brief description of the patient and their condition A typical message might say 32 M with RR 4 and sat 80 now RR 16 and 95 after Narcan ETA 10 minutes These messages give the research team the opportunity to proactively identify potential subjects We currently use a cadre of trained research assistants to monitor our ED tracking board and EMS message alerts and to provide just-in-time reminders to clinical staff about current studies We will use these research assistants to aid in subject identification These RAs are typically able to consent subjects for most studies Due to the acuity of the event and our current crowded ED state nearly all patients with an opioid OD requiring active management supplemental oxygen BVM naloxone administration are moved to our resuscitation area for rapid assessment and stabilization Once stabilized patients can be relocated to other spaces in the ED
Potential subjects will be identified by
Notification of the study team by a treating physician when a potentially eligible patient presents to the emergency department
Research assistants will monitor patient arrival alerts in TigerConnect for potentially eligible patients
Research assistants will monitor the UNMH ED tracking board for potentially eligible patients
21 Provisions to Protect the Privacy Interests of Subjects Potential subjects will be recruited from the UNM ED Whenever possible subjects will be approached in a private setting The IRB-approved study personnel responsible for approaching the potential subject about informed consent will be responsible for confirming with the patient that they are willing to discuss study participation prior to attempting to obtain informed consent All study data will be gathered directly from the subject or the subjects chart in a standard patient care area within the UNMH ED or by phone for the 7 day follow-up If the potential patient expresses privacy concerns before or during participation it will be the IRB-approved research team members responsibility to address that concern to the best of their ability and to document any steps taken to address these concerns on a study notes page Study personnel may have limited ability to address privacy concerns in certain circumstances and if they are unable to address the potential subjects privacy concerns the potential subject will be excluded from participation
22 Economic Burden to Subjects Subjects will be responsible for all costs associated with standard care they receive as part of the emergency department visit The research will cover all costs associated with research procedures UNM will not charge study subjects insurers or any other third parties for any study activities covered by the protocol and paid for by Purdue Pharma Purdue Pharma shall not be responsible for the care or treatment of any illness or injury occurring to any study subject regardless of whether such costs are otherwise covered by such study subjects medical or hospital insurance government program or other third party payor
24 Compensation for Research-Related Injury Research related injury is not expected in this study We do not expect to see higher rates of research related injury in the nalmefene or naloxone treatment arms as such there are not funds set aside for compensation in the event of research related injury In the event of research related injury subjects are responsible for seeking care UNM Hospital will provide care in the event of research related injury but subjects may seek or request care elsewhere Subjects will be responsible for the cost of that care Purdue Pharma shall not be responsible for the care or treatment of any illness or injury occurring to any Study subject regardless of whether such costs are otherwise covered by such Study subjects medical or hospital insurance government program or other third party payor
25 Consent Process Subjects are considered enrolled once they have signed and dated the IRB-approved informed consent form The consent process will take place in patient care areas in the UNMH ED Details related to maintaining patients privacy are described in Section 21 Provision to Protect the Privacy Interests of Subjects Consent will be obtained by IRB-approved study team members who are trained and delegated this task on study training and delegation logs The IRB-approved study team member obtaining informed consent will be responsible for documenting their consent discussion with the potential participant on a study notes page and confirm the subjects ability to give informed consent by completing the UCSD Brief Assessment of Capacity to Consent attached Only English-speaking subjects will be enrolled in the study Spanish-only speaking subjects will not be enrolled because it is rare for patients in the population being studied to only speak SpanishThe study will not permit consent by a legally authorized representative and will not be enrolling those who are cognitively impaired or unable to give consent This study will not include minors under the age of 18 years
26 Documentation of Consent Subject consent will be documented on a hard copy informed consent form Details of the circumstances of informed consent will be recorded on a study notes page Information substantiating a subjects ability to give informed consent will be recorded on a UCSD Brief Assessment of Capacity to Consent for each subject at the time of consent
27 Study Test ResultsIncidental Findings Individual subject research specific information will not be shared with subjects Any information relevant to their medical care will be provided by their care team The study will not generate any incidental findings that are relevant to the subjects care
28 Sharing Study Progress or Results with Subjects We do not intend to provide subjects with a summary of the trial progress while the study remains underway We do not intend to provide subjects with a summary of the study results after the study is complete
29 Inclusion of Vulnerable Populations As this study involves subjects who have experienced a suspected opioid overdose it is likely that the sample will be enriched with subjects who are economically or educationally disadvantaged The informed consent form is specifically composed to minimize use of complicated language to the greatest degree possible IRB approved study team members obtaining informed consent are responsible for ensuring the voluntariness of participation by reiterating the voluntariness of participation confirming subject understanding and eliciting questions during the process of informed consent
33 Drugs or Devices The UNMH investigational drug service is used in this study The investigational drug service allows for the secure storage and dispensation of investigational drugs in accordance with applicable state and federal regulations and institutional policies The drugs used in this investigation will be used on-label The investigational drug service will also ensure that the subjects are not billed for the investigational product
2 Number of Subjects
We will enroll 37 patients in the nalmefene group and 37 patients in the naloxone group for a total of 74 patients
Based upon our feasibility study of naloxone administrations in the ED 344 patients received naloxone in the ED during a two-year period 2021-2022 corresponding to approximately 14 patients per month Note that this is likely their 2nd dose of naloxone as nearly all patients arrive via EMS and we presume received naloxone by EMS We estimate that 75 of patients who receive opioid antagonist treatment during EMS transport or shortly after ED arrival will be capable of providing informed consent in the ED We estimate that up to 50 may decline to participate Based on these parameters we estimate enrolling 54 patients per month or 96 subjects over the 18 month enrollment period
In our power and sample size analysis we estimated we would need to enroll 62 subjects We added a 20 increase in our sample size to account for subjects that might not stay for the observation period for a total of 74 patients
To enroll 74 patients we will screen 220 patients for eligibility and consent
Sample size justification
We conducted power analyses with varying scenarios for a noninferiority clinical trial comparing nalmefene versus naloxone For a redosing rate p1 of 033 for naloxone and a redosing rate p2 of 005 for nalmefene a significance level alpha of 0025 and a margin of noninferiority of -002 we would need 31 patients in each respectively This would give us a total of 62 patients to achieve a power of 08 We will enroll 20 extra patients or 37 patients in each group in anticipation of patients not completing the observation period or the study for a total of 74 patients
3 Study Timelines
The duration of an individual subjects participation in the research 7 days
Initial visit emergency department visit with observation of 8 hours after emergency department arrival or until discharge whichever comes first
Second evaluation phone follow up at 7 days
The duration anticipated to enroll all subjects 15 years
8 Research Setting Study site Single center study at the University of New Mexico Hospital Adult Emergency Department UNMH is the only academic medical center Level I trauma center and stroke center in New Mexico UNMH is also the safety net hospital for the greater Albuquerque area The UNMH ED saw over 102000 patients in 2022 of whom 58000 were seen in the adult ED
Biological samples will be processed by TriCore Laboratories the contracted laboratory service for UNM HSC Xylazine and nitazene testing will be performed at NMS Labs nmslabscom
9 Resources Available
The UNMH emergency department is staffed 24 hours a day with licensed emergency physicians attending physicians Attending physicians will be responsible for medical decision-making and ordering and evaluation of necessary diagnostics and therapeutics for study participants
Resources
The Department of Emergency Medicine maintains a workforce of full-time trained research staff specializing in research subject identification and recruitment All staff are trained in human subject research good clinical practices and Basic Science Laboratory level 1 and 2 BSL 1-2 procedures Staff are able to accommodate regular night and weekend coverage to ensure adequate staffing to respond to potential subject enrollments
All study personnel are required to maintain current human subject protections and good clinical practices certifications and complete and document study specific training and delegation on study training and delegation logs
Pharmacy Resources The UNMH investigational drug service is used in this study The investigational drug service allows for the secure storage and dispensation of investigational drugs in accordance with applicable state and federal regulations and institutional policies
Laboratory resources The UNM HSC Clinical and Translational Sciences Center CTSC contract laboratory will be used for the processing and storage of research samples The CTSC contract laboratory provides secure 24-hour access to calibrated continuous temperature monitored freezers centrifuge and BSL-2 lab bench space Quanititative Nalmefene and Xylazine testing will be performed by NMS labs
12 Study Procedures
Screening Study subjects will be recruited from the University of New Mexico Hospital Emergency Department Research Assistants RAs will identify patients seen in the ED by reviewing the electronic medical record EMR tracking board notification by secure messaging system of arriving patients and by provider referral
Informed Consent Patients who are determined to meet all inclusion and none of the exclusion criteria will be approached about informed consent by a trained IRB-approved study team member For additional detail on informed consent see Section 21 Consent Process
Enrollment and Randomization Patients who provide written informed consent are considered enrolled in the study Subjects will be asked to complete demographics medical history and prior and concomitant medications by survey at the time of enrollment Blood Alcohol Content BAC will be measured by Breathalyzer Participants will then be randomized using the UNM Health Sciences REDCap randomization tool to either nalmefene or standard care naloxone treatment arms Research staff will be blinded to randomization
Blood Collection Blood collection for serum testing for co-ingestants xylazine and nitazenes will be performed after enrollment Blood collection for research testing will involve no more than 15 mL 1 tablespoon in up to 3 tubes at one timepoint
Subject Follow-Up RAs will remain present with the patient in the peri-dosing period to observe and record any adverse events including any occurrence of precipitated withdrawal or recrudescence for no less than 8 hours after emergency department arrival or until emergency department discharge whichever comes first Subjects will be contacted by phone 7 days - 2 days after enrollment to assess for recurrence of opioid overdose symptoms repeat emergency department visits or hospitalizations and occurrence of adverse events
Data Acquisition Demographics medical history and prior and concomitant medications adverse events will be collected by subject interviewsurvey andor observation in the ED All other data elements such as details related to medication laboratory and imagining results diagnosis and information on subsequent discharge andor hospitalization or return visit to the emergency department will be captured from the subjects EMR
13 Data Analysis Plan We will use an intention-to-treat analysis For the primary outcome we will compare the proportion of subjects experiencing the primary endpoint respiratory depression requiring opioid antagonist treatment using the Newcombes method for the difference between two proportions1 adjusted for a non-inferiority framework as the initial analysis
As we expect that the time to event respiratory depression will differ between the two treatment arms we will also compare the risk of recurrent respiratory depression using a failure time analysis Failure time analysis also known as survival analysis allows us to assess the risk of a failure event here recurrent respiratory depression while adjusting for observations that are time dependent and of varying length Failure time analyses also correctly account for incomplete observations because of a study ending or loss of subjects to follow-up we anticipate that some subjects may not stay for the full observation period For the initial analysis we anticipate using nonparametric techniques such as Kaplan-Meier curve estimation and log-rank tests to assess for differences in recurrent respiratory depression between the two arms Most frequently failure time analysis is used in situations where only one event occurs such as a diagnostic endpoint disease cure or death and the subject then is withdrawn from the study In the proposed study subjects can experience multiple failure events recurrent episodes of respiratory depression because a rescue therapy naloxone or nalmefene is available After completing the initial non-parametric analyses we propose an additional analysis that will allow us to take advantage of the likelihood that subjects may have more than one endpoint Since multiple events can occur within the same subject calculation of standard errors and statistical inference need to account for the correlation between observations in the same individual The method we propose using does this precisely and we have used this method for a different poisoningantidote study23 With this method the point estimate of the relative risk is not affected by the correlation between repeat measurements within the same individual and therefore can be calculated using a proportional hazards model All analyses will use the R statistical language
14 Provisions to Monitor the Data to Ensure the Safety of Subjects Data monitor services will be provided by the University of New Mexico Hospitals Clinical Trials Operations Office and supervised by Leslie Byatt BA CCRC PCP The study data monitor is not directly affiliated with the study
Safety monitoring will be provided by Snehal Bhatt MD Dr Bhatt is an experienced addiction medicine physician Dr Bhatt is affiliated with the University of New Mexico School of Medicine
All study subjects will be asked to stay in the UNMH Emergency Department for the duration of the 8 hour observation period All adverse events will be recorded for the duration of the 8 hour observation period All adverse event information will be prepared in summary deidentified and provided to the safety monitor on the following schedule for review
Review 1 After completion of the 3rd subject enrollment 4 of subjects enrolled Review 2 After completion of the 10th subject enrollment 14 of subjects enrolled Review 3 After completion of the 26th subject enrollment 35 of subjects enrolled Review 4 After completion of the 42nd subject enrollment 57 of subjects enrolled Review 5 After completion of the 74th and final subject enrollment 100 of subjects enrolled This safety monitor review schedule is subject to change in the event that the safety monitor raises concerns that merit more frequent reviews
All serious adverse events will be gathered through the day 7 follow-up In the event of a serious adverse event SAE that is determined to be unexpected and possibly or probably related to the investigational product enrollment will be temporarily stopped until the safety monitor has reviewed and provided recommendations related to ongoing study conduct Once any recommendations if any have been addressed the study may continue Initial SAE reports have to be reported within 24 hours of the identification of an SAE follow-up attempts will be made as needed within 3 days or no later than 14 days from the initial report if additional information becomes available this will be processed as per our procedures All SAEs will be followed to resolution All SAE information will be gathered in a detailed summary report and transmitted to the safety monitor for review Only SAEs will be forwarded to Drug Safety mailbox at AEreport2pharmacom The investigator will be using the following definitions for AEs SAEs and reportable new information The SAE report from will include start and stop date whether or not it was unexpected concise identification according to the Common Terminology for the Categorization of Adverse Events CTCAE detailed narrative description including why it is determine to meet the SAE definition below any medical interventions to address the SAE the events relationship to the study intervention and report type initial follow-up or final All SAEs must be reviewed by the principal investigator prior to submission to the safety monitor for review
Adverse Event AE Any untoward or unfavorable medical occurrence in a human study participant including any abnormal sign eg abnormal physical exam or laboratory finding symptom or disease temporally associated with the participants involvement in the research whether or not considered related to participation in the research
Serious Adverse Event SAE Any adverse event that
Results in death
Is life threatening or places the participant at immediate risk of death from the event as it occurred
Requires or prolongs hospitalization
Causes persistent or significant disability or incapacity
Results in congenital anomalies or birth defects
Is another condition which investigators judge to represent significant hazards
A pregnancy is not by definition an SAE but is handled as an SAE because it is not a condition that should occur during the clinical trial requires the subject to be discontinued from the study and requires ongoing monitoring of the pregnancy by the PI Abnormal pregnancy outcomes are considered as reportable SAEs SAEs associated with pregnancy outcome include but are not limited to
Pregnancy losses eg spontaneous abortion late fetal death elective termination
Life-threatening developments eg placental abruption fetal distress Congenital anomalies
Neonatal fatality any event resulting in maternal hospitalization prolonged hospitalization or maternal fatality
Any female subject who becomes pregnant while participating will be withdrawn from the study but will be contacted to determine the pregnancy outcome
The study team will promptly report all unanticipated problems that meet the following criteria to the UNM HSC HRRC within 5 business days of identification as reportable information Defined by DHHS 45 CFR part 46 as 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 IRB-approved research protocol and informed consent document and b the characteristics of the study population
related or possibly related to participation in the research in this guidance document possibly related means there is a reasonable possibility that the incident experience or outcome may have been caused by the procedures involved in the research
suggests that the research places participants or others at a greater risk of harm including physical psychological economic or social harm than was previously known or recognized
Subjects in the trial will receive clinical care in the UNM Hospital Emergency Department As subjects are also patients being treated for the effects of opioid intoxication all will receive standard of care Standard care includes establishing intravenous access to provide additional medication to reverse respiratory depression end-tidal carbon dioxide monitoring pulse oximetry electrocardiographic monitoring and vital sign monitoring All subjects will receive care from the ED treatment team The ED team consists of a board-certified EM faculty member resident physicians advanced practice providers emergency medicine pharmacists and registered nurses All subjects in the trial will be treated in appropriate clinical spaces within the ED A full spectrum of standard emergency equipment is readily available eg airway adjuncts advanced monitoring etc
15 Withdrawal of Subjects The study medical clinician must apply their clinical judgement to determine if an adverse event is of sufficient severity to require that the participant be withdrawn from further study participation The study medical clinician should consult with the site Principal Investigator the Co-Investigator andor Medical Monitor as needed If necessary a study medical clinician may suspend any trial treatments and institute the necessary medical therapy to protect a participant from any immediate danger
A participant may also voluntarily withdraw from treatment due to what they perceive as an intolerable adverse event or for any other reason If a voluntary withdrawal is requested the participant will be asked to complete an end-of-medication visit to assure safety and to document end-of-medication outcomes and will be given recommendations for medical care andor referrals to treatment as necessary
A participant may withdraw from any portion of the protocol eg serum collection for expanded toxicology testing but complete other aspects of the study
A participant may withdraw from the study at any time
16 Data ManagementConfidentiality All study data will be stored in accordance with all applicable state and federal regulations and in accordance with institutional requirements All subject source information will be stored NResearch-Studies network drive
The research team will have access to the patients medical record to abstract elements from the patients chart relevant to the study including patient disposition and additional AE and SAEs and 7 day follow-up data
Zip codes will not be recorded Information abstracted as part of the research study will not include direct patient identifiers ie name MRN FIN address Subjects will be identified by a unique study number A link between the patients identifying information will remain secured and stored apart from study data on the N drive This data will include substance abuse information
Data from this study will not be publicly available
All study data will be entered into UNM Health Sciences REDcap a secure web application for building and managing online surveys and databases After study closure all data will be stored in the NResearch-studies network drive
All study specimens will be labeled with a unique study ID only and stored only for the duration of testing described in this protocol Specimens will not be banked for this study and will only be accessible to IRB approved members of the study team
No data will be collected by audio or video recording Data will not include photographs This study is not funded by the NIH Data will be retained for a period of 6 years from the date the study is complete and then destroyed No minors will be included in this study
17 Data and Specimen Banking Neither data nor specimens will be banked for this study
18 Risks to Subjects
Study related risks include medication risks study procedures risks and loss of confidentiality
Medication risks associated with the use of naloxone and nalmefene are very similar and may include precipitation of severe opioid withdrawal recurrent respiratory and central nervous system depression nausea vomiting fever dizziness headache chills and vasodilation relaxingdilation of blood vessels Other risks associated with reversal of opioid overdose include cardiac related risks such as pulmonary edema fluid in the lungs cardiovascular instability hypotension low blood pressure hypertension high blood pressure tachycardia fast heart rate ventricular fibrillation irregular heart beat Risks associated with the use of nalmefene and naloxone in pregnant people include precipitated withdrawal in the fetus
Risks associated with study procedures which include a study blood draw are minimal They include pain bruising infection lightheadedness fainting blood clots and bleeding or other discomforts at the draw site
Risks associated with the possible loss of confidentiality may include emotional discomfort or stress
19 Potential Benefits to Subjects There are no known benefits to subjects
20 Recruitment Methods Potential subjects will be identified for participation in the study after presentation to the UNM ED for suspected acute opioid overdose Based upon our feasibility analyses we expect that most subjects will arrive via EMS Our dispatch team uses a secure text messaging system TigerConnect httpstigerconnectcom to alert designated staff members of pending patient arrivals based off EMS radio reports These messages typically provide a very brief description of the patient and their condition A typical message might say 32 M with RR 4 and sat 80 now RR 16 and 95 after Narcan ETA 10 minutes These messages give the research team the opportunity to proactively identify potential subjects We currently use a cadre of trained research assistants to monitor our ED tracking board and EMS message alerts and to provide just-in-time reminders to clinical staff about current studies We will use these research assistants to aid in subject identification These RAs are typically able to consent subjects for most studies Due to the acuity of the event and our current crowded ED state nearly all patients with an opioid OD requiring active management supplemental oxygen BVM naloxone administration are moved to our resuscitation area for rapid assessment and stabilization Once stabilized patients can be relocated to other spaces in the ED
Potential subjects will be identified by
Notification of the study team by a treating physician when a potentially eligible patient presents to the emergency department
Research assistants will monitor patient arrival alerts in TigerConnect for potentially eligible patients
Research assistants will monitor the UNMH ED tracking board for potentially eligible patients
21 Provisions to Protect the Privacy Interests of Subjects Potential subjects will be recruited from the UNM ED Whenever possible subjects will be approached in a private setting The IRB-approved study personnel responsible for approaching the potential subject about informed consent will be responsible for confirming with the patient that they are willing to discuss study participation prior to attempting to obtain informed consent All study data will be gathered directly from the subject or the subjects chart in a standard patient care area within the UNMH ED or by phone for the 7 day follow-up If the potential patient expresses privacy concerns before or during participation it will be the IRB-approved research team members responsibility to address that concern to the best of their ability and to document any steps taken to address these concerns on a study notes page Study personnel may have limited ability to address privacy concerns in certain circumstances and if they are unable to address the potential subjects privacy concerns the potential subject will be excluded from participation
22 Economic Burden to Subjects Subjects will be responsible for all costs associated with standard care they receive as part of the emergency department visit The research will cover all costs associated with research procedures UNM will not charge study subjects insurers or any other third parties for any study activities covered by the protocol and paid for by Purdue Pharma Purdue Pharma shall not be responsible for the care or treatment of any illness or injury occurring to any study subject regardless of whether such costs are otherwise covered by such study subjects medical or hospital insurance government program or other third party payor
24 Compensation for Research-Related Injury Research related injury is not expected in this study We do not expect to see higher rates of research related injury in the nalmefene or naloxone treatment arms as such there are not funds set aside for compensation in the event of research related injury In the event of research related injury subjects are responsible for seeking care UNM Hospital will provide care in the event of research related injury but subjects may seek or request care elsewhere Subjects will be responsible for the cost of that care Purdue Pharma shall not be responsible for the care or treatment of any illness or injury occurring to any Study subject regardless of whether such costs are otherwise covered by such Study subjects medical or hospital insurance government program or other third party payor
25 Consent Process Subjects are considered enrolled once they have signed and dated the IRB-approved informed consent form The consent process will take place in patient care areas in the UNMH ED Details related to maintaining patients privacy are described in Section 21 Provision to Protect the Privacy Interests of Subjects Consent will be obtained by IRB-approved study team members who are trained and delegated this task on study training and delegation logs The IRB-approved study team member obtaining informed consent will be responsible for documenting their consent discussion with the potential participant on a study notes page and confirm the subjects ability to give informed consent by completing the UCSD Brief Assessment of Capacity to Consent attached Only English-speaking subjects will be enrolled in the study Spanish-only speaking subjects will not be enrolled because it is rare for patients in the population being studied to only speak SpanishThe study will not permit consent by a legally authorized representative and will not be enrolling those who are cognitively impaired or unable to give consent This study will not include minors under the age of 18 years
26 Documentation of Consent Subject consent will be documented on a hard copy informed consent form Details of the circumstances of informed consent will be recorded on a study notes page Information substantiating a subjects ability to give informed consent will be recorded on a UCSD Brief Assessment of Capacity to Consent for each subject at the time of consent
27 Study Test ResultsIncidental Findings Individual subject research specific information will not be shared with subjects Any information relevant to their medical care will be provided by their care team The study will not generate any incidental findings that are relevant to the subjects care
28 Sharing Study Progress or Results with Subjects We do not intend to provide subjects with a summary of the trial progress while the study remains underway We do not intend to provide subjects with a summary of the study results after the study is complete
29 Inclusion of Vulnerable Populations As this study involves subjects who have experienced a suspected opioid overdose it is likely that the sample will be enriched with subjects who are economically or educationally disadvantaged The informed consent form is specifically composed to minimize use of complicated language to the greatest degree possible IRB approved study team members obtaining informed consent are responsible for ensuring the voluntariness of participation by reiterating the voluntariness of participation confirming subject understanding and eliciting questions during the process of informed consent
33 Drugs or Devices The UNMH investigational drug service is used in this study The investigational drug service allows for the secure storage and dispensation of investigational drugs in accordance with applicable state and federal regulations and institutional policies The drugs used in this investigation will be used on-label The investigational drug service will also ensure that the subjects are not billed for the investigational product
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None